U.S. patent number 10,183,009 [Application Number 15/592,013] was granted by the patent office on 2019-01-22 for therapeutic compounds and uses thereof.
This patent grant is currently assigned to CONSTELLATION PHARMACEUTICALS, INC., GENENTECH, INC.. The grantee listed for this patent is CONSTELLATION PHARMACEUTICALS, INC., GENENTECH, INC.. Invention is credited to Brian K. Albrecht, Steven F. Bellon, Daniel J. Burdick, Alexandre Cote, Terry Crawford, Les A. Dakin, Michael Charles Hewitt, Vickie Hsiao-Wei Tsui, Yves LeBlanc, Steven R. Magnuson, Christopher G. Nasveschuk, F. Anthony Romero, Yong Tang, Alexander M. Taylor, Shumei Wang.
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United States Patent |
10,183,009 |
Albrecht , et al. |
January 22, 2019 |
**Please see images for:
( Certificate of Correction ) ** |
Therapeutic compounds and uses thereof
Abstract
The present invention relates to compounds of formula (I):
##STR00001## and to salts thereof, wherein R.sup.1, R.sup.2, and Q
have any of the values defined in the specification, and
compositions and uses thereof. The compounds are useful as
inhibitors of bromodomains. Also included are pharmaceutical
compositions comprising a compound of formula (I) or a
pharmaceutically acceptable salt thereof, and methods of using such
compounds and salts in the treatment of various
bromodomain-mediated disorders.
Inventors: |
Albrecht; Brian K. (Cambridge,
MA), Bellon; Steven F. (Cambridge, MA), Burdick; Daniel
J. (South San Francisco, CA), Cote; Alexandre
(Cambridge, MA), Crawford; Terry (South San Francisco,
CA), Dakin; Les A. (Cambridge, MA), Hsiao-Wei Tsui;
Vickie (South San Francisco, CA), Hewitt; Michael
Charles (Cambridge, MA), LeBlanc; Yves (Cambridge,
MA), Magnuson; Steven R. (South San Francisco, CA),
Nasveschuk; Christopher G. (Cambridge, MA), Romero; F.
Anthony (South San Francisco, CA), Tang; Yong
(Cambridge, MA), Taylor; Alexander M. (Cambridge, MA),
Wang; Shumei (South San Francisco, CA) |
Applicant: |
Name |
City |
State |
Country |
Type |
GENENTECH, INC.
CONSTELLATION PHARMACEUTICALS, INC. |
South San Francisco
Cambridge |
CA
MA |
US
US |
|
|
Assignee: |
GENENTECH, INC. (South San
Francisco, CA)
CONSTELLATION PHARMACEUTICALS, INC. (Cambridge, MA)
|
Family
ID: |
54608969 |
Appl.
No.: |
15/592,013 |
Filed: |
May 10, 2017 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20170340605 A1 |
Nov 30, 2017 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
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PCT/US2015/060003 |
Nov 10, 2015 |
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62077703 |
Nov 10, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P
29/00 (20180101); A61P 3/10 (20180101); A61P
17/00 (20180101); C07D 471/04 (20130101); A61P
19/02 (20180101); A61P 5/06 (20180101); A61P
1/04 (20180101); A61P 5/38 (20180101); A61P
37/02 (20180101); A61P 19/00 (20180101); A61P
19/06 (20180101); A61P 1/18 (20180101); A61P
9/10 (20180101); A61P 13/12 (20180101); A61P
35/02 (20180101); A61P 37/06 (20180101); A61P
19/08 (20180101); A61P 1/00 (20180101); A61K
31/40 (20130101); A61P 35/00 (20180101); A61P
11/00 (20180101); A61P 11/06 (20180101); A61P
43/00 (20180101); A61P 1/16 (20180101); A61P
9/00 (20180101); A61P 17/06 (20180101); A61P
37/00 (20180101); A61P 5/14 (20180101) |
Current International
Class: |
A61K
31/40 (20060101); C07D 471/04 (20060101) |
References Cited
[Referenced By]
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Oct 2015 |
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WO |
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|
Primary Examiner: Pagano; Alexander R
Attorney, Agent or Firm: Viksnins Harris Padys Malen LLP
Claims
We claim:
1. A compound of formula (I): ##STR00264## or a salt thereof,
wherein: R.sup.1 is methyl substituted with one or more groups
R.sup.m, ethyl substituted with one or more groups R.sup.n,
C.sub.3-12alkyl, C.sub.2-12alkenyl, C.sub.2-12alkynyl, or
heterocyclyl, wherein any C.sub.3-12alkyl, C.sub.2-12alkenyl,
C.sub.2-12alkynyl, or heterocyclyl of R.sup.1 is optionally
substituted with one or more groups R.sup.a; R.sup.2 is H,
C.sub.1-12alkyl, C.sub.2-12alkenyl, C.sub.2-12alkynyl, or
C.sub.3-8cycloalkyl, wherein each C.sub.1-12alkyl,
C.sub.2-12alkenyl, C.sub.2-12alkynyl, or C.sub.3-8cycloalkyl of
R.sup.2 is optionally substituted with one or more groups R.sup.b;
Q is carbocyclyl or heterocyclyl, which carbocyclyl or heterocyclyl
is optionally substituted with one or more groups R.sup.c; each
R.sup.a is independently selected from the group consisting of oxo,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6haloalkyl, carbocyclyl, heterocyclyl, --F, --Cl, --Br,
--I, --NO.sub.2, --N(R.sup.v).sub.2, --CN,
--C(O)--N(R.sup.v).sub.2, --S(O)--N(R.sup.v).sub.2,
--S(O).sub.2--N(R.sup.v).sub.2, --O--R.sup.v, --S--R.sup.v,
--O--C(O)--R.sup.v, --O--C(O)--O--R.sup.v, --C(O)--R.sup.v,
--C(O)--O--R.sup.v, --S(O)--R.sup.v, --S(O).sub.2--R.sup.v,
--O--C(O)--N(R.sup.v).sub.2, --N(R.sup.v)--C(O)--OR.sup.v,
--N(R.sup.v)--C(O)--N(R.sup.v).sub.2, --N(R.sup.v)--C(O)--R.sup.v,
--N(R.sup.v)--S(O)--R.sup.v, --N(R.sup.v)--S(O).sub.2--R.sup.v,
--N(R.sup.v)--S(O)--N(R.sup.v).sub.2, and
--N(R.sup.v)--S(O).sub.2--N(R.sup.v).sub.2; each R.sup.b is
independently selected from the group consisting of oxo,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6haloalkyl, carbocyclyl, heterocyclyl, --F, --Cl, --Br,
--I, --NO.sub.2, --N(R.sup.w).sub.2, --CN,
--C(O)--N(R.sup.w).sub.2, --S(O)--N(R.sup.w).sub.2,
--S(O).sub.2--N(R.sup.w).sub.2, --O--R.sup.w, --S--R.sup.w,
--O--C(O)--R.sup.w, --O--C(O)--O--R.sup.w, --C(O)--R.sup.w,
--C(O)--O--R.sup.w, --S(O)--R.sup.w, --S(O).sub.2--R.sup.w,
--O--C(O)--N(R.sup.w).sub.2, --N(R.sup.w)--C(O)--OR.sup.w,
--N(R.sup.w)--C(O)--N(R.sup.w).sub.2, --N(R.sup.w)--C(O)--R.sup.w,
--N(R.sup.w)--S(O)--R.sup.w, --N(R.sup.w)--S(O).sub.2--R.sup.w,
--N(R.sup.w)--S(O)--N(R.sup.w).sub.2, and
--N(R.sup.w)--S(O).sub.2--N(R.sup.w).sub.2, wherein any
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6haloalkyl, carbocyclyl, or heterocyclyl of R.sup.b is
optionally substituted with one or more groups independently
selected from the group consisting of oxo, halo, --NO.sub.2,
--N(R.sup.w).sub.2, --CN, --C(O)--N(R.sup.w).sub.2,
--S(O)--N(R.sup.w).sub.2, --S(O).sub.2--N(R.sup.w).sub.2,
--O--R.sup.w, --S--R.sup.w, --O--C(O)--R.sup.w, --C(O)--R.sup.w,
--C(O)--O--R.sup.w, --S(O)--R.sup.w, --S(O).sub.2--R.sup.w,
--C(O)--N(R.sup.w).sub.2, --N(R.sup.w)--C(O)--R.sup.w,
--N(R.sup.w)--S(O)--R.sup.w, --N(R.sup.w)--S(O).sub.2--R.sup.w and
C.sub.1-6alkyl that is optionally substituted with one or more
groups independently selected from the group consisting of oxo and
halo; each R.sup.c is independently selected from the group
consisting of oxo, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.1-6haloalkyl, carbocyclyl, heterocyclyl,
--F, --Cl, --Br, --I, --NO.sub.2, --N(R.sup.u).sub.2, --CN,
--C(O)--N(R.sup.u).sub.2, --S(O)--N(R.sup.u).sub.2,
--S(O).sub.2--N(R.sup.u).sub.2, --O--R.sup.u, --S--R.sup.u,
--O--C(O)--R.sup.u, --O--C(O)--O--R.sup.u, --C(O)--R.sup.u,
--C(O)--O--R.sup.u, --S(O)--R.sup.u, --S(O).sub.2--R.sup.u,
--O--C(O)--N(R.sup.u).sub.2, --N(R.sup.u)--C(O)--OR.sup.u,
--N(R.sup.u)--C(O)--N(R.sup.u).sub.2, --N(R.sup.u)--S(O)--R.sup.u,
--N(R.sup.u)--S(O).sub.2--R.sup.u,
--N(R.sup.u)--S(O)--N(R.sup.u).sub.2, and
--N(R.sup.u)--S(O).sub.2--N(R.sup.u).sub.2, wherein any
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6haloalkyl, carbocyclyl, or heterocyclyl of R is optionally
substituted with one or more groups independently selected from the
group consisting of oxo, halo, --NO.sub.2, --N(R.sup.u).sub.2,
--CN, --C(O)--N(R.sup.u).sub.2, --S(O)--N(R.sup.u).sub.2,
--S(O).sub.2--N(R.sup.u).sub.2, --O--R.sup.u, --S--R.sup.u,
--O--C(O)--R.sup.u, --C(O)--R.sup.u, --C(O)--O--R.sup.u,
--S(O)--R.sup.u, --S(O).sub.2--R.sup.u,
--N(R.sup.u)--C(O)--R.sup.u, --N(R.sup.u)--S(O)--R.sup.u,
--N(R.sup.u)--S(O).sub.2--R.sup.u and C.sub.1-6alkyl that is
optionally substituted with one or more groups independently
selected from the group consisting of oxo and halo; each R.sup.m is
independently selected from the group consisting of oxo,
carbocyclyl, heterocyclyl, --F, --NO.sub.2, --CN,
--C(O)--N(R.sup.v).sub.2, --S(O)--N(R.sup.v).sub.2,
--S(O).sub.2--N(R.sup.v).sub.2, --C(O)--R.sup.v,
--C(O)--O--R.sup.v, --S(O)--R.sup.v, and --S(O).sub.2--R.sup.v,
wherein carbocyclyl is optionally substituted with one or more
--O--R.sup.v; each R.sup.n is independently selected from the group
consisting of oxo, carbocyclyl, heterocyclyl, --F, --Cl, --Br, --I,
--NO.sub.2, --N(R.sup.v).sub.2, --CN, --C(O)--N(R.sup.v).sub.2,
--S(O)--N(R.sup.v).sub.2, --S(O).sub.2--N(R.sup.v).sub.2,
--O--R.sup.v, --S--R.sup.v, --O--C(O)--R.sup.v,
--O--C(O)--O--R.sup.v, --C(O)--R.sup.v, --C(O)--O--R.sup.v,
--S(O)--R.sup.v, --S(O).sub.2--R.sup.v,
--O--C(O)--N(R.sup.v).sub.2, --N(R.sup.v)--C(O)--OR.sup.v,
--N(R.sup.v)--C(O)--N(R.sup.v).sub.2, --N(R.sup.v)--C(O)--R.sup.v,
--N(R.sup.v)--S(O)--R.sup.v, --N(R.sup.v)--S(O).sub.2--R.sup.v,
--N(R.sup.v)--S(O)--N(R.sup.v).sub.2, and
--N(R.sup.v)--S(O).sub.2--N(R.sup.v).sub.2; each R.sup.u is
independently selected from the group consisting of hydrogen,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, carbocyclyl,
and heterocyclyl, wherein each C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, carbocyclyl, or heterocyclyl of R.sup.u is
optionally substituted with one or more groups independently
selected from the group consisting of oxo, halo,
--N(R.sup.ua).sub.2, hydroxyl, carbocyclyl, heterocyclyl, and
C.sub.1-C.sub.6 alkyl that is optionally substituted with one or
more groups independently selected from the group consisting of oxo
and halo; or two R.sup.u are taken together with the nitrogen to
which they are attached to form a heterocyclyl that is optionally
substituted with one or more groups independently selected from the
group consisting of oxo, halo, C.sub.1-3alkyl and heteroaryl
wherein C.sub.1-3alkyl is optionally substituted with one or more
groups independently selected from the group consisting of oxo,
hydroxyl, --N(R.sup.ua).sub.2, halo, and heteroaryl that is
optionally substituted with one or more --N(R.sup.ua).sub.2; each
R.sup.v is independently selected from the group consisting of
hydrogen, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
carbocyclyl, and heterocyclyl, wherein each C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, carbocyclyl, or heterocyclyl of
R.sup.v is optionally substituted with one or more groups
independently selected from the group consisting of oxo, halo,
--N(R.sup.va).sub.2, hydroxyl, carbocyclyl, heterocyclyl, and
C.sub.1-C.sub.6 alkyl that is optionally substituted with one or
more groups independently selected from the group consisting of oxo
and halo; or two R.sup.v are taken together with the nitrogen to
which they are attached to form a heterocyclyl that is optionally
substituted with one or more groups independently selected from the
group consisting of oxo, halo and C.sub.1-3alkyl that is optionally
substituted with one or more groups independently selected from the
group consisting of oxo and halo; each R.sup.w is independently
selected from the group consisting of hydrogen, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, carbocyclyl, and heterocyclyl,
wherein each C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
carbocyclyl, or heterocyclyl of R.sup.w is optionally substituted
with one or more groups independently selected from the group
consisting of oxo, halo, --N(R.sup.wa).sub.2, hydroxyl, and
C.sub.1-C.sub.6 alkyl that is optionally substituted with one or
more groups independently selected from the group consisting of oxo
and halo; or two R.sup.w are taken together with the nitrogen to
which they are attached to form a heterocyclyl that is optionally
substituted with one or more groups independently selected from the
group consisting of oxo, halo and C.sub.1-3alkyl that is optionally
substituted with one or more groups independently selected from the
group consisting of oxo and halo; each R.sup.ua is independently
selected from the group consisting of hydrogen and C.sub.1-6alkyl;
each R.sup.va is independently selected from the group consisting
of hydrogen and C.sub.1-6alkyl; and each R.sup.wa is independently
selected from the group consisting of hydrogen and
C.sub.1-6alkyl.
2. The compound of claim 1 wherein R.sup.1 is methyl that is
substituted with one or more groups R.sup.m.
3. The compound of claim 1 wherein R.sup.1 is ethyl that is
substituted with one or more groups R.sup.n.
4. The compound of claim 1 wherein R.sup.1 is butyl,
2-cyclopropylethyl, cyclopentylmethyl, 2-penten-1-yl,
cyclohexylmethyl, cyclobutylmethyl, 2-cyclohexylethyl, pentyl,
2-methylpropyl, 2-buten-1-yl, butyl, 2-furylmethyl,
3-methylbut-1-yl, 2-propenyl, 3-methyl-2-buten-1-yl, 3-buten-1-yl,
2-methoxyethyl, 3-methoxypropyl, or 4-methoxybenzyl.
5. The compound of claim 1 wherein R.sup.2 is methyl.
6. The compound of claim 1 wherein Q is C.sub.3-C.sub.8cycloalkyl
that is optionally substituted with one or more groups R.sup.c.
7. The compound of claim 1 wherein Q is aryl that is optionally
substituted with one or more groups R.sup.c.
8. The compound of claim 1 wherein Q is phenyl that is optionally
substituted with one or more groups R.sup.c.
9. The compound of claim 1 wherein Q is
C.sub.3-C.sub.8heterocycloalkyl that is optionally substituted with
one or more groups R.sup.c.
10. The compound of claim 1 wherein Q is heteroaryl that is
optionally substituted with one or more groups R.sup.c.
11. The compound of claim 1 wherein Q is: ##STR00265## wherein:
ring A is optionally substituted with one or more groups R.sup.g,
or ring A is optionally fused with a carbocyclyl or a heterocyclyl
to form a polycyclyl that is optionally substituted with one or
more groups R.sup.g; R.sup.e is hydrogen, --F, --Cl, --Br, --I,
--CN, --O--R.sup.x, C.sub.1-6alkyl, C.sub.2-6alkenyl, or
C.sub.2-6alkynyl, wherein each C.sub.1-6alkyl, C.sub.2-6alkenyl, or
C.sub.2-6alkynyl is optionally substituted with one or more groups
independently selected from the group consisting of oxo, --F, --Cl,
--Br, --I, --NO.sub.2, --N(R.sup.x).sub.2, --CN,
--C(O)--N(R.sup.x).sub.2, --S(O)--N(R.sup.x).sub.2,
--S(O).sub.2--N(R.sup.x).sub.2, --O--R.sup.x, --S--R.sup.x,
--O--C(O)--R.sup.x, --C(O)--R.sup.x, --C(O)--O--R.sup.x,
--S(O)--R.sup.x, --S(O).sub.2--R.sup.x,
--N(R.sup.x)--C(O)--R.sup.x, --N(R.sup.x)--S(O)--R.sup.x, and
--N(R.sup.x)--S(O).sub.2--R.sup.x; R.sup.f is hydrogen, --F, --Cl,
--Br, --I, --CN, --O--R.sup.y, C.sub.1-6alkyl, C.sub.2-6alkenyl, or
C.sub.2-6alkynyl, wherein each C.sub.1-6alkyl, C.sub.2-6alkenyl, or
C.sub.2-6alkynyl is optionally substituted with one or more groups
independently selected from the group consisting of oxo, --F, --Cl,
--Br, --I, --NO.sub.2, --N(R.sup.y).sub.2, --CN,
--C(O)--N(R.sup.y).sub.2, --S(O)--N(R.sup.y).sub.2,
--S(O).sub.2--N(R.sup.y).sub.2, --O--R.sup.y, --S--R.sup.y,
--O--C(O)--R.sup.y, --C(O)--R.sup.y, --C(O)--O--R.sup.y,
--S(O)--R.sup.y, --S(O).sub.2--R.sup.y,
--N(R.sup.y)--C(O)--R.sup.y, --N(R.sup.y)--S(O)--R.sup.y and
--N(R.sup.y)--S(O).sub.2--R.sup.y; each R.sup.g is independently
selected from the group consisting of oxo, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6haloalkyl,
carbocyclyl, heterocyclyl, --F, --Cl, --Br, --I, --NO.sub.2,
--N(R.sup.z).sub.2, --CN, --C(O)--N(R.sup.z).sub.2,
--S(O)--N(R.sup.z).sub.2, --S(O).sub.2--N(R.sup.z).sub.2,
--O--R.sup.z, --S--R.sup.z, --O--C(O)--R.sup.z,
--O--C(O)--O--R.sup.z, --C(O)--R.sup.z, --C(O)--O--R.sup.z,
--S(O)--R.sup.z, --S(O).sub.2--R.sup.z,
--O--C(O)--N(R.sup.z).sub.2, --N(R.sup.z)--C(O)--OR.sup.z,
--N(R.sup.z)--C(O)--N(R.sup.z).sub.2, --N(R.sup.z)--C(O)--R.sup.z,
--N(R.sup.z)--S(O)--R.sup.z, --N(R.sup.z)--S(O).sub.2--R.sup.z,
--N(R.sup.z)--S(O)--N(R.sup.z).sub.2, and
--N(R.sup.z)--S(O).sub.2--N(R.sup.z).sub.2, wherein any
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6haloalkyl, carbocyclyl, or heterocyclyl of R.sup.g is
optionally substituted with one or more groups independently
selected from the group consisting of oxo, halo, --NO.sub.2,
--N(R.sup.z).sub.2, --CN, --C(O)--N(R.sup.z).sub.2,
--S(O)--N(R.sup.z).sub.2, --S(O).sub.2--N(R.sup.z).sub.2,
--O--R.sup.z, --S--R.sup.z, --O--C(O)--R.sup.z, --C(O)--R.sup.z,
--C(O)--O--R.sup.z, --S(O)--R.sup.z, --S(O).sub.2--R.sup.z,
--N(R.sup.z)--C(O)--R.sup.z, --N(R.sup.z)--S(O)--R.sup.z,
--N(R.sup.z)--S(O).sub.2--R.sup.z and C.sub.1-6alkyl and heteroaryl
wherein C.sub.1-3alkyl is optionally substituted with one or more
groups independently selected from the group consisting of oxo,
hydroxyl, --N(R.sup.ua).sub.2, halo, and heteroaryl that is
optionally substituted with one or more --N(R.sup.ua).sub.2; each
R.sup.x is independently selected from the group consisting of
hydrogen, C.sub.1-6alkyl, C.sub.2-6alkenyl, and C.sub.2-6alkynyl,
wherein each C.sub.1-6alkyl, C.sub.2-6alkenyl, or C.sub.2-6alkynyl
is optionally substituted with one or more groups independently
selected from the group consisting of oxo, halo, amino, hydroxyl,
and C.sub.1-C.sub.6 alkyl; each R.sup.y is independently selected
from the group consisting of hydrogen, C.sub.1-6alkyl,
C.sub.2-6alkenyl, and C.sub.2-6alkynyl, wherein each
C.sub.1-6alkyl, C.sub.2-6alkenyl, or C.sub.2-6alkynyl is optionally
substituted with one or more groups independently selected from the
group consisting of oxo, halo, amino, hydroxyl, and C.sub.1-C.sub.6
alkyl; and each R.sup.z is independently selected from the group
consisting of hydrogen, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, carbocyclyl, and heterocyclyl, wherein each
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, carbocyclyl, or
heterocyclyl is optionally substituted with one or more groups
independently selected from the group consisting of oxo, halo,
amino, hydroxyl, heterocyclyl, carbocyclyl, and C.sub.1-C.sub.6
alkyl that is optionally substituted with one or more groups
independently selected from the group consisting of oxo and halo;
or two R.sup.z are taken together with the nitrogen to which they
are attached to form a heterocyclyl that is optionally substituted
with one or more groups independently selected from the group
consisting of oxo, halo and C.sub.1-3alkyl that is optionally
substituted with one or more groups independently selected from the
group consisting of oxo and halo.
12. The compound of claim 1, wherein each R.sup.c is independently
selected from the group consisting of oxo, C.sub.1-6alkyl,
heterocyclyl, --F, --Cl, --CN, --C(O)--N(R.sup.u).sub.2,
--O--R.sup.u, and --N(R.sup.u)--S(O).sub.2--R.sup.u, wherein any
C.sub.1-6alkyl or heterocyclyl is optionally substituted with one
or more groups independently selected from the group consisting of
--O--R.sup.u and C.sub.1-6alkyl that is optionally substituted with
one or more groups independently selected from the group consisting
of oxo and halo.
13. The compound of claim 1 wherein Q is selected from the group
consisting of: ##STR00266## ##STR00267## ##STR00268## ##STR00269##
##STR00270## ##STR00271## ##STR00272## ##STR00273##
##STR00274##
14. The compound of claim 1 that is selected from the group
consisting of:
3-(6-allyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N,N-dimethylbenzamide-
;
3-(6-butyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N,N-dimethylbenzamide;
N,N-dimethyl-3-[6-(3-methylbut-2-enyl)-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-y-
l]benzamide;
3-[6-(2-cyclopropylethyl)-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N,N-dimeth-
ylbenzamide;
3-[6-(cyclopentylmethyl)-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N,N-dimethy-
lbenzamide;
3-[6-[(4-methoxyphenyl)methyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N,N-d-
imethylbenzamide;
N,N-dimethyl-3-[7-oxo-6-[(E)-pent-2-enyl]-1H-pyrrolo[2,3-c]pyridin-4-yl]b-
enzamide;
3-(6-but-3-enyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N,N-dimethy-
lbenzamide;
3-[6-(cyclohexylmethyl)-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N,N-dimethyl-
benzamide;
3-(6-isopentyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N,N-dimethy-
lbenzamide;
3-[6-(cyclobutylmethyl)-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N,N-dimethyl-
benzamide;
3-[6-(2-cyclohexylethyl)-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N-
,N-dimethylbenzamide;
N,N-dimethyl-3-(7-oxo-6-pentyl-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide;
3-[6-(2-methoxyethyl)-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N,N-dimethylbe-
nzamide;
3-[6-(3-methoxypropyl)-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N,N-d-
imethylbenzamide;
3-(6-isobutyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N,N-dimethylbenzamide;
3-[6-(cyclopropylmethyl)-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N,N-dimethy-
lbenzamide;
6-but-3-enyl-4-[3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]-1H-pyrrolo[2,3-c-
]pyridin-7-one;
3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-5-fluoro-N,N-d-
imethylbenzamide;
4-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-2-fluorobenzam-
ide;
6-but-2-enyl-4-[4-(4-methylpiperazine-1-carbonyl)phenyl]-1H-pyrrolo[2-
,3-c]pyridin-7-one;
3-(6-but-2-enyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-5-fluorobenzamide;
6-but-2-enyl-4-(4-tert-butylphenyl)-1H-pyrrolo[2,3-c]pyridin-7-one;
4-(6-but-2-enyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-methylbenzamide;
3-(6-but-2-enyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-methylbenzamide;
3-(6-but-2-enyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-cyclopropylbenzami-
de;
6-but-2-enyl-4-[3-(pyrrolidine-1-carbonyl)phenyl]-1H-pyrrolo[2,3-c]pyr-
idin-7-one;
4-(6-but-2-enyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-cyclopropylbenzami-
de;
6-but-2-enyl-4-[4-(hydroxymethyl)phenyl]-1H-pyrrolo[2,3-c]pyridin-7-on-
e; 3-(6-but-2-enyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide;
6-but-2-enyl-4-(4-isopropylphenyl)-1H-pyrrolo[2,3-c]pyridin-7-one;
3-(6-but-2-enyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N,N-dimethylbenzamid-
e;
6-but-2-enyl-4-[4-(pyrrolidine-1-carbonyl)phenyl]-1H-pyrrolo[2,3-c]pyri-
din-7-one;
N-[4-(6-but-2-enyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]m-
ethanesulfonamide;
3-(6-but-2-enyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-isopropylbenzamide-
;
4-(6-but-2-enyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N,N-dimethylbenzami-
de;
6-but-2-enyl-4-[4-(morpholine-4-carbonyl)phenyl]-1H-pyrrolo[2,3-c]pyri-
din-7-one;
3-(6-but-2-enyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-methoxy--
benzonitrile;
3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-2-fluorobenzam-
ide;
3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-4-fluorobe-
nzamide;
3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-4-fluo-
ro-N,N-dimethylbenzamide;
3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-2-fluoro-N,N-d-
imethylbenzamide;
4-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-2-chloro-N,N-d-
imethylbenzamide;
4-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-2-chlorobenzam-
ide; 6-(2-furylmethyl)-4-phenyl-1H-pyrrolo[2,3-c]pyridin-7-one;
3-(6-butyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-methoxy-benzonitrile;
3-[6-(2-cyclopropylethyl)-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-4-methoxy--
benzonitrile;
3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N-cyclopropyl--
4-methoxybenzamide;
3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-4-methoxy-N,N--
dimethylbenzamide;
3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-4-methoxy-N-te-
trahydrofuran-3-ylbenzamide;
3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N-ethyl-4-meth-
oxybenzamide;
3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-4-methoxy-N-me-
thylbenzamide;
6-[(E)-but-2-enyl]-4-[2-methoxy-5-(pyrrolidine-1-carbonyl)phenyl]-1H-pyrr-
olo[2,3-c]pyridin-7-one;
3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N-(2,2-difluor-
oethyl)-4-methoxybenzamide;
3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N-isobutyl-4-m-
ethoxybenzamide;
4-[5-(azetidine-1-carbonyl)-2-methoxy-phenyl]-6-[(E)-but-2-enyl]-1H-pyrro-
lo[2,3-c]pyridin-7-one;
3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N-[2-(dimethyl-
amino)ethyl]-4-methoxybenzamide;
3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N-(2-hydroxyet-
hyl)-4-methoxybenzamide;
3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-4-methoxy-N-pr-
opylbenzamide;
3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N-cyclobutyl-4-
-methoxybenzamide;
3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N-(cyclopropyl-
methyl)-4-methoxybenzamide;
4-[5-(6-acetyl-2,6-diazaspiro[3.3]heptane-2-carbonyl)-2-methoxy-phenyl]-6-
-[(E)-but-2-enyl]-1H-pyrrolo[2,3-c]pyridin-7-one;
4-[5-(6-acetyl-2,6-diazaspiro[3.3]heptane-2-carbonyl)-2-methoxy-phenyl]-6-
-butyl-1H-pyrrolo[2,3-c]pyridin-7-one;
6-[(E)-but-2-enyl]-4-[4-(1-hydroxy-1-methyl-ethyl)-2-methoxy-phenyl]-1H-p-
yrrolo[2,3-c]pyridin-7-one;
6-butyl-4-[4-(1-hydroxy-1-methyl-ethyl)-2-methoxy-phenyl]-1H-pyrrolo[2,3--
c]pyridin-7-one;
6-[(E)-but-2-enyl]-4-[4-(1-hydroxy-1-methyl-ethyl)phenyl]-1H-pyrrolo[2,3--
c]pyridin-7-one;
6-butyl-4-(4-(2-hydroxypropan-2-yl)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-
-one;
6-(2-cyclopropylethyl)-4-[4-(1-hydroxy-1-methyl-ethyl)phenyl]-1H-pyr-
rolo[2,3-c]pyridin-7-one;
3-(6-(2-cyclopropylethyl)-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyr-
idin-4-yl)-N,N-dimethylbenzamide;
3-(6-butyl-2-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N,N-dimethylbenz-
amide;
3-(6-butyl-2-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-methoxy--
N,N-dimethylbenzamide;
3-[6-(2-cyclopropylethyl)-2-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-4-
-methoxy-N,N-dimethylbenzamide;
7-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-4-methyl-1,3,4-
,5-tetrahydro-1,5-benzodiazepin-2-one;
6-but-3-enyl-4-[3,4-difluoro-5-(morpholine-4-carbonyl)phenyl]-1H-pyrrolo[-
2,3-c]pyridin-7-one;
6-but-3-enyl-4-[3-fluoro-5-(3-methylmorpholine-4-carbonyl)phenyl]-1H-pyrr-
olo[2,3-c]pyridin-7-one;
3-(6-but-3-enyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-5-(morpholine-4-carb-
onyl)benzonitrile
6-[(E)-but-2-enyl]-4-[3-chloro-4-(morpholine-4-carbonyl)phenyl]-1H-pyrrol-
o[2,3-c]pyridin-7-one;
6-[(E)-but-2-enyl]-4-[3-chloro-4-(pyrrolidine-1-carbonyl)phenyl]-1H-pyrro-
lo[2,3-c]pyridin-7-one;
6-but-3-enyl-4-[3-fluoro-5-(morpholine-4-carbonyl)phenyl]-1H-pyrrolo[2,3--
c]pyridin-7-one;
6-but-3-enyl-4-[4-fluoro-3-(morpholine-4-carbonyl)phenyl]-1H-pyrrolo[2,3--
c]pyridin-7-one;
6-but-3-enyl-4-[3-(difluoromethoxy)-5-(morpholine-4-carbonyl)phenyl]-1H-p-
yrrolo[2,3-c]pyridin-7-one;
6-but-3-enyl-4-[6-(morpholine-4-carbonyl)-1H-benzimidazol-4-yl]-1H-pyrrol-
o[2,3-c]pyridin-7-one;
7-(6-but-3-enyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N,N-dimethyl-3H-benz-
imidazole-5-carboxamide;
6-but-3-enyl-4-[7-(morpholine-4-carbonyl)-3H-benzimidazol-5-yl]-1H-pyrrol-
o[2,3-c]pyridin-7-one;
6-but-3-enyl-4-[3-methyl-7-(morpholine-4-carbonyl)benzimidazol-5-yl]-1H-p-
yrrolo[2,3-c]pyridin-7-one;
6-but-3-enyl-4-[3-ethyl-7-(morpholine-4-carbonyl)benzimidazol-5-yl]-1H-py-
rrolo[2,3-c]pyridin-7-one;
6-but-3-enyl-4-[1-methyl-7-(morpholine-4-carbonyl)benzimidazol-5-yl]-1H-p-
yrrolo[2,3-c]pyridin-7-one;
6-but-3-enyl-4-[1-methyl-6-(morpholine-4-carbonyl)benzimidazol-4-yl]-1H-p-
yrrolo[2,3-c]pyridin-7-one;
6-but-3-enyl-4-[4-chloro-3-(morpholine-4-carbonyl)phenyl]-2-methyl-1H-pyr-
rolo[2,3-c]pyridin-7-one;
6-[(E)-but-2-enyl]-2-methyl-4-[4-(morpholine-4-carbonyl)phenyl]-1H-pyrrol-
o[2,3-c]pyridin-7-one;
6-[(E)-but-2-enyl]-2-methyl-4-[4-(pyrrolidine-1-carbonyl)phenyl]-1H-pyrro-
lo[2,3-c]pyridin-7-one
6-[(E)-but-2-enyl]-4-[3-chloro-4-(pyrrolidine-1-carbonyl)phenyl]-2-methyl-
-1H-pyrrolo[2,3-c]pyridin-7-one;
6-[(E)-but-2-enyl]-4-[2,3-difluoro-4-(morpholine-4-carbonyl)phenyl]-2-met-
hyl-1H-pyrrolo[2,3-c]pyridin-7-one;
6-[(E)-but-2-enyl]-4-[3-methoxy-4-(morpholine-4-carbonyl)phenyl]-2-methyl-
-1H-pyrrolo[2,3-c]pyridin-7-one;
6-[(E)-but-2-enyl]-4-[3-chloro-4-(morpholine-4-carbonyl)phenyl]-2-methyl--
1H-pyrrolo[2,3-c]pyridin-7-one;
6-but-3-enyl-4-[3-fluoro-5-(morpholine-4-carbonyl)phenyl]-2-methyl-1H-pyr-
rolo[2,3-c]pyridin-7-one;
6-but-3-enyl-4-[4-fluoro-3-(morpholine-4-carbonyl)phenyl]-2-methyl-1H-pyr-
rolo[2,3-c]pyridin-7-one;
6-[(E)-but-2-enyl]-4-[5-chloro-6-(morpholine-4-carbonyl)-3-pyridyl]-2-met-
hyl-1H-pyrrolo[2,3-c]pyridin-7-one;
6-[(E)-but-2-enyl]-4-[3-chloro-4-(4-methylpiperazine-1-carbonyl)phenyl]-2-
-methyl-1H-pyrrolo[2,3-c]pyridin-7-one;
6-[(E)-but-2-enyl]-2-methyl-4-[3-methyl-4-(morpholine-4-carbonyl)phenyl]--
1H-pyrrolo[2,3-c]pyridin-7-one;
6-allyl-4-[3-chloro-4-(morpholine-4-carbonyl)phenyl]-2-methyl-1H-pyrrolo[-
2,3-c]pyridin-7-one;
6-allyl-4-[2,5-dimethoxy-4-(morpholine-4-carbonyl)phenyl]-2-methyl-1H-pyr-
rolo[2,3-c]pyridin-7-one;
6-[(E)-but-2-enyl]-4-[3-methoxy-5-(morpholine-4-carbonyl)-2-pyridyl]-2-me-
thyl-1H-pyrrolo[2,3-c]pyridin-7-one;
6-[(E)-but-2-enyl]-4-[4-chloro-5-(morpholine-4-carbonyl)-2-pyridyl]-2-met-
hyl-1H-pyrrolo[2,3-c]pyridin-7-one;
6-[(E)-but-2-enyl]-2-methyl-4-[2-(morpholine-4-carbonyl)pyrimidin-5-yl]-1-
H-pyrrolo[2,3-c]pyridin-7-one;
5-[6-[(E)-but-2-enyl]-2-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-2-(mo-
rpholine-4-carbonyl)benzonitrile;
6-[(E)-but-2-enyl]-4-[4-(1-hydroxy-1-methyl-ethyl)-2-methoxy-phenyl]-2-me-
thyl-1H-pyrrolo[2,3-c]pyridin-7-one
6-[(E)-but-2-enyl]-4-[2,5-dimethoxy-4-(morpholine-4-carbonyl)phenyl]-2-me-
thyl-1H-pyrrolo[2,3-c]pyridin-7-one;
3-[6-[(E)-but-2-enyl]-2-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-4-met-
hoxy-N-(pyrazin-2-ylmethyl)benzamide
6-but-2-enyl-4-[3-methoxy-5-(4-methylpiperazine-1-carbonyl)-2-pyridyl]-2--
methyl-1H-pyrrolo[2,3-c]pyridin-7-one;
6-[(E)-but-2-enyl]-4-[6-chloro-5-(morpholine-4-carbonyl)-2-pyridyl]-2-met-
hyl-1H-pyrrolo[2,3-c]pyridin-7-one;
1-[4-[6-[(E)-but-2-enyl]-2-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-2--
chloro-benzoyl]piperidine-4-carboxylic acid;
1-[4-[6-[(E)-but-2-enyl]-2-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-2--
chloro-benzoyl]piperidine-4-carboxamide;
6-[(E)-but-2-enyl]-4-[3-isopropoxy-4-(morpholine-4-carbonyl)phenyl]-2-met-
hyl-1H-pyrrolo[2,3-c]pyridin-7-one;
6-[(E)-but-2-enyl]-4-[3-(cyclopropylmethoxy)-4-(morpholine-4-carbonyl)phe-
nyl]-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-one;
6-[(E)-but-2-enyl]-4-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-2-methyl--
1H-pyrrolo[2,3-c]pyridin-7-one;
4-[4-[3-(3-aminopyrazol-1-yl)azetidine-1-carbonyl]-3-chloro-phenyl]-6-[(E-
)-but-2-enyl]-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-one;
4-[4-[3-(3-aminopyrazol-1-yl)azetidine-1-carbonyl]phenyl]-6-[(E)-but-2-en-
yl]-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-one;
6-[(E)-but-2-enyl]-4-[4-(1-hydroxy-1-methyl-ethyl)-2,5-dimethoxy-phenyl]--
2-methyl-1H-pyrrolo[2,3-c]pyridin-7-one;
3-[6-[(E)-but-2-enyl]-2-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-4-met-
hoxy-N-(pyrimidin-5-ylmethyl)benzamide;
6-butyl-4-[2,5-dimethoxy-4-(morpholine-4-carbonyl)phenyl]-2-methyl-1H-pyr-
rolo[2,3-c]pyridin-7-one;
6-butyl-4-[3-methoxy-5-(4-methylpiperazine-1-carbonyl)-2-pyridyl]-2-methy-
l-1H-pyrrolo[2,3-c]pyridin-7-one; and
6-butyl-4-[3-methoxy-5-(morpholine-4-carbonyl)-2-pyridyl]-2-methyl-1H-pyr-
rolo[2,3-c]pyridin-7-one; or a salt thereof.
15. A composition comprising a compound of formula (I) as described
in claim 1 or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable adjuvant, carrier, or vehicle.
16. A method for treating a bromodomain-mediated disorder in an
animal comprising administering a compound of formula (I), or a
pharmaceutically acceptable salt thereof as described in claim 1,
to the animal, wherein the bromodomain-mediated disorder is
cancer.
17. A method of increasing efficacy of a cancer treatment
comprising a cytotoxic agent in an animal comprising administering
to the animal an effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt thereof as described in claim
1.
18. A method of delaying or preventing development of cancer
resistance to a cytotoxic agent in an animal, comprising
administering to the animal a compound of formula (I) or a
pharmaceutically acceptable salt thereof as described in claim
1.
19. A method of extending the duration of response to a cancer
therapy in an animal, comprising administering to an animal
undergoing the cancer therapy a compound of formula (I) or a
pharmaceutically acceptable salt thereof, as described in claim 1,
wherein the duration of response to the cancer therapy when the
compound of formula (I) or the pharmaceutically acceptable salt
thereof is administered is extended over the duration of response
to the cancer therapy in the absence of the administration of the
compound of formula (I) or the pharmaceutically acceptable salt
thereof.
20. A method of treating cancer in an individual comprising
administering to the individual (a) a compound of formula (I) or a
pharmaceutically acceptable salt thereof as described in claim 1,
and (b) a cytotoxic agent.
21. The compound of claim 1, wherein each R.sup.c is independently
selected from the group consisting of oxo, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6haloalkyl,
carbocyclyl, heterocyclyl, --F, --Cl, --N(R.sup.u).sub.2, --CN,
--C(O)--N(R.sup.u).sub.2, --O--R.sup.u, and
--N(R.sup.u)--S(O).sub.2--R.sup.u, wherein any C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6haloalkyl,
carbocyclyl, or heterocyclyl is optionally substituted with one or
more groups independently selected from the group consisting of
oxo, halo, --NO.sub.2, --N(R.sup.u).sub.2, --CN,
--C(O)--N(R.sup.u).sub.2, --S(O)--N(R.sup.u).sub.2,
--S(O).sub.2--N(R.sup.u).sub.2, --O--R.sup.u, --S--R.sup.u,
--O--C(O)--R.sup.u, --C(O)--R.sup.u, --C(O)--O--R.sup.u,
--S(O)--R.sup.u, --S(O).sub.2--R.sup.u,
--N(R.sup.u)--C(O)--R.sup.u, --N(R.sup.u)--S(O)--R.sup.u,
--N(R.sup.u)--S(O).sub.2--R.sup.u, and C.sub.1-6alkyl that is
optionally substituted with one or more groups independently
selected from the group consisting of oxo and halo.
22. The compound of claim 1, wherein each R is independently
selected from the group consisting of oxo, C.sub.1-6alkyl,
heterocyclyl, --F, --Cl, --CN, --C(O)--N(R.sup.u).sub.2,
--O--R.sup.u, and --N(R.sup.u)--S(O).sub.2--R.sup.u, wherein any
C.sub.1-6alkyl or heterocyclyl is optionally substituted with one
or more groups independently selected from the group consisting of
oxo, halo, --NO.sub.2, --N(R.sup.u).sub.2, --CN,
--C(O)--N(R.sup.u).sub.2, --S(O)--N(R.sup.u).sub.2,
--S(O).sub.2--N(R.sup.u).sub.2, --O--R.sup.u, --S--R.sup.u,
--O--C(O)--R.sup.u, --C(O)--R.sup.u, --C(O)--O--R.sup.u,
--S(O)--R.sup.u, --S(O).sub.2--R.sup.u,
--N(R.sup.u)--C(O)--R.sup.u, --N(R.sup.u)--S(O)--R.sup.u,
--N(R.sup.u)--S(O).sub.2--R.sup.u and C.sub.1-6alkyl that is
optionally substituted with one or more groups independently
selected from the group consisting of oxo and halo.
Description
CROSS-REFERENCE TO RELATED APPLICATION(S)
This patent application is a continuation of International
Application No. PCT/US2015/060003, filed Nov. 10, 2015, which
claims the benefit of priority of U.S. application Ser. No.
62/077,703, filed Nov. 10, 2014, which applications are herein
incorporated by reference.
TECHNICAL FIELD OF THE INVENTION
The present invention relates to compounds useful as inhibitors of
bromodomains.
BACKGROUND OF THE INVENTION
Chromatin is a complex combination of DNA and protein that makes up
chromosomes. It is found inside the nuclei of eukaryotic cells and
is divided between heterochromatin (condensed) and euchromatin
(extended) forms. The major components of chromatin are DNA and
proteins. Histones are the chief protein components of chromatin,
acting as spools around which DNA winds. The functions of chromatin
are to package DNA into a smaller volume to fit in the cell, to
strengthen the DNA to allow mitosis and meiosis, and to serve as a
mechanism to control expression and DNA replication. The chromatin
structure is controlled by a series of post-translational
modifications to histone proteins, notably histones H3 and H4, and
most commonly within the "histone tails" which extend beyond the
core nucleosome structure. Histone tails tend to be free for
protein-protein interaction and are also the portion of the histone
most prone to post-translational modification. These modifications
include acetylation, methylation, phosphorylation,
ubiquitinylation, and SUMOylation. These epigenetic marks are
written and erased by specific enzymes that place the tags on
specific residues within the histone tail, thereby forming an
epigenetic code, which is then interpreted by the cell to allow
gene specific regulation of chromatin structure and thereby
transcription.
Of all classes of proteins, histones are amongst the most
susceptible to post-translational modification. Histone
modifications are dynamic, as they can be added or removed in
response to specific stimuli, and these modifications direct both
structural changes to chromatin and alterations in gene
transcription. Distinct classes of enzymes, namely histone
acetyltransferases (HATs) and histone deacetylases (HDACs),
acetylate or de-acetylate specific histone lysine residues (Struhl
K., Genes Dev., 1989, 12, 5, 599-606).
Bromodomains, which are approximately 110 amino acids long, are
found in a large number of chromatin-associated proteins and have
been identified in approximately 70 human proteins, often adjacent
to other protein motifs (Jeanmougin F., et al., Trends Biochem.
Sci., 1997, 22, 5, 151-153; and Tamkun J. W., et al., Cell, 1992,
7, 3, 561-572). Interactions between bromodomains and modified
histones may be an important mechanism underlying chromatin
structural changes and gene regulation. Bromodomain-containing
proteins have been implicated in disease processes including
cancer, inflammation and viral replication. See, e.g., Prinjha et
al., Trends Pharm. Sci., 33(3):146-153 (2012) and Muller et al.,
Expert Rev., 13(29):1-20 (September 2011).
Cell-type specificity and proper tissue functionality requires the
tight control of distinct transcriptional programs that are
intimately influenced by their environment. Alterations to this
transcriptional homeostasis are directly associated with numerous
disease states, most notably cancer, immuno-inflammation,
neurological disorders, and metabolic diseases. Bromodomains reside
within key chromatin modifying complexes that serve to control
distinctive disease-associated transcriptional pathways. This is
highlighted by the observation that mutations in
bromodomain-containing proteins are linked to cancer, as well as
immune and neurologic dysfunction. Moreover, recent findings have
demonstrated that small molecule inhibition of the bromodomains of
BRD4 may have clinical utility in diverse human diseases, ranging
from auto-immunity to cardiac hypertrophy. This is possible because
the underlying mechanism resides in transcriptional regulation.
Hence, the selective inhibition of bromodomains across the family
creates varied opportunities as novel therapeutic agents in human
dysfunction.
There is a need for treatments for cancer, immunological disorders,
and other bromodomain related diseases.
SUMMARY OF THE INVENTION
One aspect includes a compound of formula (I):
##STR00002## or a salt thereof, wherein:
R.sup.1 is methyl, ethyl, C.sub.3-12alkyl, C.sub.2-12alkenyl,
C.sub.2-12alkynyl, carbocyclyl, or heterocyclyl, wherein any methyl
of R.sup.1 is substituted with one or more groups R.sup.m, wherein
any ethyl of R.sup.1 is substituted with one or more groups
R.sup.n, and wherein any C.sub.3-12alkyl, C.sub.2-12alkenyl,
C.sub.2-12alkynyl, carbocyclyl or heterocyclyl of R.sup.1 is
optionally substituted with one or more groups R.sup.1;
R.sup.2 is H, C.sub.1-12alkyl, C.sub.2-12alkenyl,
C.sub.2-12alkynyl, or C.sub.3-8cycloalkyl, wherein each
C.sub.1-12alkyl, C.sub.2-12alkenyl, C.sub.2-12alkynyl, or
C.sub.3-8cycloalkyl of R.sup.2 is optionally substituted with one
or more groups R.sup.b;
Q is carbocyclyl or heterocyclyl, which carbocyclyl or heterocyclyl
is optionally substituted with one or more groups R.sup.c;
each R.sup.a is independently selected from oxo, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6haloalkyl,
carbocyclyl, heterocyclyl, --F, --Cl, --Br, --I, --NO.sub.2,
--N(R.sup.v).sub.2, --CN, --C(O)--N(R.sup.v).sub.2,
--S(O)--N(R.sup.v).sub.2, --S(O).sub.2--N(R.sup.v).sub.2,
--O--R.sup.v, --S--R.sup.v, --O--C(O)--R.sup.v,
--O--C(O)--O--R.sup.v, --C(O)--R.sup.v, --C(O)--O--R.sup.v,
--S(O)--R.sup.v, --S(O).sub.2--R.sup.v,
--O--C(O)--N(R.sup.v).sub.2, --N(R.sup.v)--C(O)--OR.sup.v,
--N(R.sup.v)--C(O)--N(R.sup.v).sub.2, --N(R.sup.v)--C(O)--R.sup.v,
--N(R.sup.v)--S(O)--R.sup.v, --N(R.sup.v)--S(O).sub.2--R.sup.v,
--N(R.sup.v)--S(O)--N(R.sup.v).sub.2, and
--N(R.sup.v)--S(O).sub.2--N(R.sup.v).sub.2;
each R.sup.b is independently selected from oxo, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6haloalkyl,
carbocyclyl, heterocyclyl, --F, --Cl, --Br, --I, --NO.sub.2,
--N(R.sup.w).sub.2, --CN, --C(O)--N(R.sup.w).sub.2,
--S(O)--N(R.sup.w).sub.2, --S(O).sub.2--N(R.sup.w).sub.2,
--O--R.sup.w, --S--R.sup.w, --O--C(O)--R.sup.w,
--O--C(O)--O--R.sup.w, --C(O)--R.sup.w, --C(O)--O--R.sup.w,
--S(O)--R.sup.w, --S(O).sub.2--R.sup.w,
--O--C(O)--N(R.sup.w).sub.2, --N(R.sup.w)--C(O)--OR.sup.w,
--N(R.sup.w)--C(O)--N(R.sup.w).sub.2, --N(R.sup.w)--C(O)--R.sup.w,
--N(R.sup.w)--S(O)--R.sup.w, --N(R.sup.w)--S(O).sub.2--R.sup.w,
--N(R.sup.w)--S(O)--N(R.sup.w).sub.2, and
--N(R.sup.w)--S(O).sub.2--N(R.sup.w).sub.2, wherein any
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6haloalkyl, carbocyclyl, or heterocyclyl is optionally
substituted with one or more groups independently selected from
oxo, halo, --NO.sub.2, --N(R.sup.w).sub.2, --CN,
--C(O)--N(R.sup.w).sub.2, --S(O)--N(R.sup.w).sub.2,
--S(O).sub.2--N(R.sup.w).sub.2, --O--R.sup.w, --S--R.sup.w,
--O--C(O)--R.sup.w, --C(O)--R.sup.w, --C(O)--O--R.sup.w,
--S(O)--R.sup.w, --S(O).sub.2--R.sup.w, --C(O)--N(R.sup.w).sub.2,
--N(R.sup.w)--C(O)--R.sup.w, --N(R.sup.w)--S(O)--R.sup.w,
--N(R.sup.w)--S(O).sub.2--R.sup.w and C.sub.1-6alkyl that is
optionally substituted with one or more groups independently
selected from oxo and halo;
each R.sup.c is independently selected from oxo, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6haloalkyl,
carbocyclyl, heterocyclyl, --F, --Cl, --Br, --I, --NO.sub.2,
--N(R.sup.u).sub.2, --CN, --C(O)--N(R.sup.u).sub.2,
--S(O)--N(R.sup.u).sub.2, --S(O).sub.2--N(R.sup.u).sub.2,
--O--R.sup.u, --S--R.sup.u, --O--C(O)--R.sup.u,
--O--C(O)--O--R.sup.u, --C(O)--R.sup.u, --C(O)--O--R.sup.u,
--S(O)--R.sup.u, --S(O).sub.2--R.sup.u,
--O--C(O)--N(R.sup.u).sub.2, --N(R.sup.u)--C(O)--OR.sup.u,
--N(R.sup.u)--C(O)--N(R.sup.u).sub.2, --N(R.sup.u)--C(O)--R.sup.u,
--N(R.sup.u)--S(O)--R.sup.u, --N(R.sup.u)--S(O).sub.2--R.sup.u,
--N(R.sup.u)--S(O)--N(R.sup.u).sub.2, and
--N(R.sup.u)--S(O).sub.2--N(R.sup.u).sub.2, wherein any
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6haloalkyl, carbocyclyl, or heterocyclyl is optionally
substituted with one or more groups independently selected from
oxo, halo, --NO.sub.2, --N(R.sup.u).sub.2, --CN,
--C(O)--N(R.sup.u).sub.2, --S(O)--N(R.sup.u).sub.2,
--S(O).sub.2--N(R.sup.u).sub.2, --O--R.sup.u, --S--R.sup.u,
--O--C(O)--R.sup.u, --C(O)--R.sup.u, --C(O)--O--R.sup.u,
--S(O)--R.sup.u, --S(O).sub.2--R.sup.u,
--N(R.sup.u)--C(O)--R.sup.u, --N(R.sup.u)--S(O)--R.sup.u,
--N(R.sup.u)--S(O).sub.2--R.sup.u and C.sub.1-6alkyl that is
optionally substituted with one or more groups independently
selected from oxo and halo;
each R.sup.m is independently selected from oxo, carbocyclyl,
heterocyclyl, --F, --NO.sub.2, --CN, --C(O)--N(R.sup.v).sub.2,
--S(O)--N(R.sup.v).sub.2, --S(O).sub.2--N(R.sup.v).sub.2,
--C(O)--R.sup.v, --C(O)--O--R.sup.v, --S(O)--R.sup.v, and
--S(O).sub.2--R.sup.v, wherein carbocyclyl is optionally
substituted with one or more --O--R.sup.v;
each R.sup.n is independently selected from oxo, carbocyclyl,
heterocyclyl, --F, --Cl, --Br, --I, --NO.sub.2, --N(R.sup.v).sub.2,
--CN, --C(O)--N(R.sup.v).sub.2, --S(O)--N(R.sup.v).sub.2,
--S(O).sub.2--N(R.sup.v).sub.2, --O--R.sup.v, --S--R.sup.v,
--O--C(O)--R.sup.v, --O--C(O)--O--R.sup.v, --C(O)--R.sup.v,
--C(O)--O--R.sup.v, --S(O)--R.sup.v, --S(O).sub.2--R.sup.v,
--O--C(O)--N(R.sup.v).sub.2, --N(R.sup.v)--C(O)--N(R.sup.v).sub.2,
and --N(R.sup.v)--S(O).sub.2--N(R.sup.v).sub.2;
each R.sup.u is independently selected from hydrogen,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, carbocyclyl,
and heterocyclyl, wherein each C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, carbocyclyl, or heterocyclyl is optionally
substituted with one or more groups independently selected from
oxo, halo, --N(R.sup.ua).sub.2, hydroxyl, carbocyclyl,
heterocyclyl, and C.sub.1-C.sub.6 alkyl that is optionally
substituted with one or more groups independently selected from oxo
and halo; or two R.sup.u are taken together with the nitrogen to
which they are attached to form a heterocyclyl that is optionally
substituted with one or more groups independently selected from
oxo, halo, C.sub.1-3alkyl and heteroaryl wherein C.sub.1-3alkyl is
optionally substituted with one or more groups independently
selected from oxo, hydroxyl, --N(R.sup.ua).sub.2 and halo and
heteroaryl is optionally substituted with one or more
--N(R.sup.ua).sub.2;
each R.sup.v is independently selected from hydrogen,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, carbocyclyl,
and heterocyclyl, wherein each C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, carbocyclyl, or heterocyclyl is optionally
substituted with one or more groups independently selected from
oxo, halo, --N(R.sup.va).sub.2, hydroxyl, carbocyclyl,
heterocyclyl, and C.sub.1-C.sub.6 alkyl that is optionally
substituted with one or more groups independently selected from oxo
and halo; or two R.sup.v are taken together with the nitrogen to
which they are attached to form a heterocyclyl that is optionally
substituted with one or more groups independently selected from
oxo, halo and C.sub.1-3alkyl that is optionally substituted with
one or more groups independently selected from oxo and halo;
each R.sup.w is independently selected from hydrogen,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, carbocyclyl,
and heterocyclyl, wherein each C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, carbocyclyl, or heterocyclyl is optionally
substituted with one or more groups independently selected from
oxo, halo, --N(R.sup.va).sub.2, hydroxyl, and C.sub.1-C.sub.6 alkyl
that is optionally substituted with one or more groups
independently selected from oxo and halo; or two R.sup.w are taken
together with the nitrogen to which they are attached to form a
heterocyclyl that is optionally substituted with one or more groups
independently selected from oxo, halo and C.sub.1-3alkyl that is
optionally substituted with one or more groups independently
selected from oxo and halo;
each R.sup.ua is independently selected from hydrogen and
C.sub.1-6alkyl;
each R.sup.va is independently selected from hydrogen and
C.sub.1-6alkyl; and
each R.sup.wa is independently selected from hydrogen and
C.sub.1-6alkyl.
Another aspect includes a composition comprising a compound of
formula (I) or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable adjuvant, carrier, or vehicle.
Another aspect includes a method for treating a
bromodomain-mediated disorder in an animal comprising administering
a compound of formula (I) or a pharmaceutically acceptable salt
thereof to the animal.
Another aspect includes a compound of formula (I) or a
pharmaceutically acceptable salt thereof for use in medical
therapy.
Another aspect includes a compound of formula (I) or a
pharmaceutically acceptable salt thereof for the prophylactic or
therapeutic treatment of a bromodomain-mediated disorder.
Another aspect includes the use of a compound of formula (I) or a
pharmaceutically acceptable salt thereof to prepare a medicament
for treating a bromodomain-mediated disorder in an animal (e.g. a
mammal such as a human).
Another aspect includes compounds for the study of
bromodomains.
Another aspect includes synthetic intermediates and synthetic
processes disclosed herein that are useful for preparing a compound
of formula (I) or a salt thereof.
DETAILED DESCRIPTION
Compounds and Definitions
Definitions and terms are described in more detail below. Chemical
elements are identified in accordance with the Periodic Table of
the Elements, CAS version, Handbook of Chemistry and Physics,
75.sup.th Ed.
Unless otherwise stated, compounds of formula I include
enantiomeric, diastereomeric and geometric (or conformational)
isomeric forms of a given structure. For example, the R and S
configurations for each asymmetric center, Z and E double bond
isomers, Z and E conformational isomers, single stereochemical
isomers, as well as enantiomeric, diastereomeric, and geometric (or
conformational) mixtures are included. Unless otherwise stated, all
tautomeric forms of structures depicted herein are included.
Additionally, unless otherwise stated, structures depicted herein
are also meant to include compounds that differ only in the
presence of one or more isotopically enriched atoms. For example,
compounds of formula I, wherein the independent replacement or
enrichment of one or more hydrogen by deuterium or tritium, carbon
by .sup.13C- or .sup.14C carbon, nitrogen by a .sup.15N nitrogen,
sulfur by a .sup.33S, .sup.34S or .sup.36S sulfur, or oxygen by a
.sup.17O or .sup.18O oxygen are included. Such compounds are
useful, for example, as analytical tools, as probes in biological
assays, or as therapeutic agents.
Where a particular enantiomer is described, it may, in certain
embodiments be provided substantially free of the corresponding
enantiomer, and may also be referred to as "optically enriched."
"Optically-enriched," as used herein, means that the mixture of
enantiomers is made up of a significantly greater proportion of one
enantiomer, and may be described by enantiomeric excess (ee %). In
certain embodiments, the mixture of enantiomers is made up of at
least about 90% by weight of a given enantiomer (about 90% ee). In
other embodiments, the mixture of enantiomers is made up of at
least about 95%, 98% or 99% by weight of a given enantiomer (about
95%, 98% or 99% ee). Enantiomers and diastereomers may be isolated
from racemic mixtures by any method known to those skilled in the
art, including recrystallization from solvents in which one
stereoisomer is more soluble than the other, chiral high pressure
liquid chromatography (HPLC), supercritical fluid chromatography
(SFC), the formation and crystallization of chiral salts, which are
then separated by any of the above methods, or prepared by
asymmetric syntheses and optionally further enriched. See, for
example, Jacques et al., Enantiomers, Racemates and Resolutions
(Wiley Interscience, New York, 1981); Wilen, et al., Tetrahedron
33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon Compounds
(McGraw-Hill, NY, 1962); Wilen, S. H. Tables of Resolving Agents
and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre
Dame Press, Notre Dame, Ind. 1972).
The term "heteroatom" means any atom independently selected from an
atom other than carbon or hydrogen, for example, one or more of
oxygen, sulfur, nitrogen, phosphorus or silicon (including any
oxidized form of nitrogen, sulfur, phosphorus or silicon; and the
quaternized form of any nitrogen).
The terms "halo" and "halogen" as used herein refer to an atom
selected from fluorine (fluoro, --F), chlorine (chloro, --Cl),
bromine (bromo, --Br) and iodine (iodo, --I).
The term "oxo" refers to .dbd.O or (.dbd.O).sub.2.
The term "unsaturated", as used herein, means that a moiety has one
or more units of unsaturation.
The term "carbocyclyl" used alone or as part of a larger moiety,
refers to a saturated, partially unsaturated, or aromatic ring
system having 3 to 20 carbon atoms. In one embodiment, carbocyclyl
includes 3 to 12 carbon atoms (C.sub.3-C.sub.12). In another
embodiment, carbocyclyl includes C.sub.3-C.sub.8, C.sub.3-C.sub.10
or C.sub.5-C.sub.10. In other embodiment, carbocyclyl, as a
monocycle, includes C.sub.3-C.sub.8, C.sub.3-C.sub.6 or
C.sub.5-C.sub.6. In another embodiment, carbocyclyl, as a bicycle,
includes C.sub.7-C.sub.2. In another embodiment, carbocyclyl, as a
spiro system, includes C.sub.5-C.sub.12. Examples of monocyclic
carbocyclyls include cyclopropyl, cyclobutyl, cyclopentyl,
1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl,
cyclohexyl, perdeuteriocyclohexyl, 1-cyclohex-1-enyl,
1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl,
cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, phenyl, and
cyclododecyl; bicyclic carbocyclyls having 7 to 12 ring atoms
include [4,3], [4,4], [4,5], [5,5], [5,6] or [6,6] ring systems,
for example bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane,
naphthalene, and bicyclo[3.2.2]nonane; and spiro carbocyclyls
include spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane,
spiro[2.5]octane and spiro[4.5]decane. The term carbocyclyl
includes aryl ring systems as defined herein. The term carbocycyl
also includes cycloalkyl rings (e.g. saturated or partially
unsaturated mono-, bi-, or spiro-carbocycles).
The term "alkyl," as used herein, refers to a saturated linear or
branched-chain monovalent hydrocarbon radical. In one embodiment,
the alkyl radical is one to eighteen carbon atoms
(C.sub.1-C.sub.18). In other embodiments, the alkyl radical is
C.sub.0-C.sub.6, C.sub.0-C.sub.5, C.sub.0-C.sub.3,
C.sub.1-C.sub.12, C.sub.1-C.sub.10, C.sub.1-C.sub.8,
C.sub.1-C.sub.6, C.sub.1-C.sub.5, C.sub.1-C.sub.4 or
C.sub.1-C.sub.3. C.sub.0 alkyl refers to a bond. Examples of alkyl
groups include methyl (Me, --CH.sub.3), ethyl (Et,
--CH.sub.2CH.sub.3), 1-propyl (n-Pr, n-propyl,
--CH.sub.2CH.sub.2CH.sub.3), 2-propyl (i-Pr, i-propyl,
--CH(CH.sub.3).sub.2), 1-butyl (n-Bu, n-butyl,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-methyl-1-propyl (i-Bu,
i-butyl, --CH.sub.2CH(CH.sub.3).sub.2), 2-butyl (s-Bu, s-butyl,
--CH(CH.sub.3)CH.sub.2CH.sub.3), 2-methyl-2-propyl (t-Bu, t-butyl,
--C(CH.sub.3).sub.3), 1-pentyl (n-pentyl,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-pentyl
(--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.3), 3-pentyl
(--CH(CH.sub.2CH.sub.3).sub.2), 2-methyl-2-butyl
(--C(CH.sub.3).sub.2CH.sub.2CH.sub.3), 3-methyl-2-butyl
(--CH(CH.sub.3)CH(CH.sub.3).sub.2), 3-methyl-1-butyl
(--CH.sub.2CH.sub.2CH(CH.sub.3).sub.2), 2-methyl-1-butyl
(--CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.3), I-hexyl
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-hexyl
(--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 3-hexyl
(--CH(CH.sub.2CH.sub.3)(CH.sub.2CH.sub.2CH.sub.3)),
2-methyl-2-pentyl (--C(CH.sub.3).sub.2CH.sub.2CH.sub.2CH.sub.3),
3-methyl-2-pentyl (--CH(CH.sub.3)CH(CH.sub.3)CH.sub.2CH.sub.3),
4-methyl-2-pentyl (--CH(CH.sub.3)CH.sub.2CH(CH.sub.3).sub.2),
3-methyl-3-pentyl (--C(CH.sub.3)(CH.sub.2CH.sub.3).sub.2),
2-methyl-3-pentyl (--CH(CH.sub.2CH.sub.3)CH(CH.sub.3).sub.2),
2,3-dimethyl-2-butyl (--C(CH.sub.3).sub.2CH(CH.sub.3).sub.2),
3,3-dimethyl-2-butyl (--CH(CH.sub.3)C(CH.sub.3).sub.3, heptyl,
octyl, nonyl, decyl, undecyl and dodecyl.
The term "alkenyl," as used herein, denotes a linear or
branched-chain monovalent hydrocarbon radical with at least one
carbon-carbon double bond. An alkenyl includes radicals having
"cis" and "trans" orientations, or alternatively, "E" and "Z"
orientations. In one example, the alkenyl radical is two to
eighteen carbon atoms (C.sub.2-C.sub.18). In other examples, the
alkenyl radical is C.sub.2-C.sub.12, C.sub.2-C.sub.10,
C.sub.2-C.sub.8, C.sub.2-C.sub.6 or C.sub.2-C.sub.3. Examples
include, but are not limited to, ethenyl or vinyl
(--CH.dbd.CH.sub.2), prop-1-enyl (--CH.dbd.CHCH.sub.3), prop-2-enyl
(--CH.sub.2CH.dbd.CH.sub.2), 2-methylprop-1-enyl, but-1-enyl,
but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-diene,
hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl and
hexa-1,3-dienyl.
The term "alkynyl," as used herein, refers to a linear or branched
monovalent hydrocarbon radical with at least one carbon-carbon
triple bond. In one example, the alkynyl radical is two to eighteen
carbon atoms (C.sub.2-C.sub.18). In other examples, the alkynyl
radical is C.sub.2-C.sub.12, C.sub.2-C.sub.10, C.sub.2-C.sub.8,
C.sub.2-C.sub.6 or C.sub.2-C.sub.3. Examples include, but are not
limited to, ethynyl (--C.ident.CH), prop-1-ynyl
(--C.ident.CCH.sub.3), prop-2-ynyl (propargyl,
--CH.sub.2C.ident.CH), but-1-ynyl, but-2-ynyl and but-3-ynyl.
The term "alkoxy" refers to a linear or branched monovalent radical
represented by the formula --OR in which R is alkyl, alkenyl,
alkynyl or carbocycyl. Alkoxy groups include methoxy, ethoxy,
propoxy, isopropoxy, and cyclopropoxy.
The term "haloalkyl," as used herein, refers to an alkyl as defined
herein that is substituted with one or more (e.g. 1, 2, 3, or 4)
halo groups.
The term "aryl" used alone or as part of a larger moiety as in
"arylalkyl", "arylalkoxy", or "aryloxyalkyl", refers to a
monocyclic, bicyclic or tricyclic, carbon ring system, that
includes fused rings, wherein at least one ring in the system is
aromatic. The term "aryl" may be used interchangeably with the term
"aryl ring". In one embodiment, aryl includes groups having 6-18
carbon atoms. In another embodiment, aryl includes groups having
6-10 carbon atoms. Examples of aryl groups include phenyl,
naphthyl, anthracyl, biphenyl, phenanthrenyl, naphthacenyl,
1,2,3,4-tetrahydronaphthalenyl, 1H-indenyl, 2,3-dihydro-1H-indenyl,
and the like, which may be substituted or independently substituted
by one or more substituents described herein. A particular aryl is
phenyl. In another embodiment aryl includes an aryl ring fused to
one or more carbocyclic rings, such as indanyl, or
tetrahydronaphthyl, and the like, where the radical or point of
attachment is on an aromatic ring.
The term "heteroaryl" used alone or as part of a larger moiety,
e.g., "heteroarylalkyl", or "heteroarylalkoxy", refers to a
monocyclic, bicyclic or tricyclic ring system having 5 to 14 ring
atoms, wherein at least one ring is aromatic and contains at least
one heteroatom. In one embodiment, heteroaryl includes 4-6 membered
monocyclic aromatic groups where one or more ring atoms is
nitrogen, sulfur or oxygen that is independently optionally
substituted. In another embodiment, heteroaryl includes 5-6
membered monocyclic aromatic groups where one or more ring atoms is
nitrogen, sulfur or oxygen that is independently optionally
substituted. Example heteroaryl groups include thienyl, furyl,
imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl,
isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl,
thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl,
pyridazinyl, triazinyl, tetrazinyl, tetrazolo[1,5-b]pyridazinyl,
imidazol[1,2-a]pyrimidinyl, purinyl, benzoxazolyl, benzofuryl,
benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoimidazolyl,
indolyl, 1,3-thiazol-2-yl, 1,3,4-triazol-5-yl, 1,3-oxazol-2-yl,
1,3,4-oxadiazol-5-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-5-yl,
1H-tetrazol-5-yl, 1,2,3-triazol-5-yl, and pyrid-2-yl N-oxide. The
terms "heteroaryl" also includes groups in which a heteroaryl is
fused to one or more aryl, carbocyclyl, or heterocyclyl rings,
where the radical or point of attachment is on the heteroaryl ring.
Nonlimiting examples include indolyl, isoindolyl, benzothienyl,
benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,
benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,
quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl,
phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. A
heteroaryl group may be mono-, bi- or tri-cyclic.
As used herein, the term "heterocyclyl" refers to a "carbocyclyl"
as defined herein, wherein one or more (e.g. 1, 2, 3, or 4) carbon
atoms have been replaced with a heteroatom (e.g. O, N, or S). In
some embodiments, a heterocyclyl refers to a saturated ring system,
such as a 3 to 12 membered saturated heterocyclyl ring system. In
some embodiments, a heterocyclyl refers to a heteroaryl ring
system, such as a 5 to 14 membered heteroaryl ring system. A
heterocyclyl can optionally be substituted with one or more
substituents independently selected from those defined herein. The
term heterocyclyl also includes C.sub.3-C.sub.8heterocycloalkyl,
which is a saturated or partially unsaturated mono-, bi-, or
spiro-ring system comprising 3-8 carbons and one or more (1, 2, 3,
or 4) heteroatoms.
In one example, heterocyclyl includes 3-12 ring atoms and includes
monocycles, bicycles, tricycles and spiro ring systems, wherein the
ring atoms are carbon, and one to five ring atoms is a heteroatom
selected from nitrogen, sulfur or oxygen, which is independently
optionally substituted by one or more groups. In one example,
heterocyclyl includes 1 to 4 heteroatoms. In another example,
heterocyclyl includes 3- to 7-membered monocycles having one or
more heteroatoms selected from nitrogen, sulfur or oxygen. In
another example, heterocyclyl includes 4- to 6-membered monocycles
having one or more heteroatoms selected from nitrogen, sulfur or
oxygen. In another example, heterocyclyl includes 3-membered
monocycles. In another example, heterocyclyl includes 4-membered
monocycles. In another example, heterocyclyl includes 5-6 membered
monocycles. In one example, the heterocyclyl group includes 0 to 3
double bonds. Any nitrogen or sulfur heteroatom may optionally be
oxidized (e.g. NO, SO, SO.sub.2), and any nitrogen heteroatom may
optionally be quaternized (e.g. [NR.sub.4].sup.+Cl.sup.-,
[NR.sub.4].sup.+OH.sup.-). Example heterocyclyls include oxiranyl,
aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl,
1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl,
dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl,
dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl,
piperazinyl, morpholinyl, thiomorpholinyl,
1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl,
hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinanyl,
thiazinanyl, thioxanyl, homopiperazinyl, homopiperidinyl, azepanyl,
oxepanyl, thiepanyl, oxazepinyl, oxazepanyl, diazepanyl,
1,4-diazepanyl, diazepinyl, thiazepinyl, thiazepanyl,
tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl,
isothiazolidinyl, 1,1-dioxoisothiazolidinonyl, oxazolidinonyl,
imidazolidinonyl, 4,5,6,7-tetrahydro[2H]indazolyl,
tetrahydrobenzoimidazolyl, 4,5,6,7-tetrahydrobenzo[d]imidazolyl,
1,6-dihydroimidazol[4,5-d]pyrrolo[2,3-b]pyridinyl, thiazinyl,
oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl,
oxathiazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl,
imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl,
2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiapyranyl, 2H-pyranyl,
4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl,
dithianyl, dithiolanyl, pyrimidinonyl, pyrimidindionyl,
pyrimidin-2,4-dionyl, piperazinonyl, piperazindionyl,
pyrazolidinylimidazolinyl, 3-azabicyclo[3.1.0]hexanyl,
3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl,
3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl,
azabicyclo[2.2.2]hexanyl, 2-azabicyclo[3.2.1]octanyl,
8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]octanyl,
8-azabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptane,
azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]decanyl,
I-azaspiro[4.5]decan-2-only, azaspiro[5.5]undecanyl,
tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl,
tetrahydroindazolyl, 1,1-dioxohexahydrothiopyranyl. Examples of
5-membered heterocyclyls containing a sulfur or oxygen atom and one
to three nitrogen atoms are thiazolyl, including thiazol-2-yl and
thiazol-2-yl N-oxide, thiadiazolyl, including 1,3,4-thiadiazol-5-yl
and 1,2,4-thiadiazol-5-yl, oxazolyl, for example oxazol-2-yl, and
oxadiazolyl, such as 1,3,4-oxadiazol-5-yl, and
1,2,4-oxadiazol-5-yl. Example 5-membered ring heterocyclyls
containing 2 to 4 nitrogen atoms include imidazolyl, such as
imidazol-2-yl; triazolyl, such as 1,3,4-triazol-5-yl;
1,2,3-triazol-5-yl, 1,2,4-triazol-5-yl, and tetrazolyl, such as
1H-tetrazol-5-yl. Example benzo-fused 5-membered heterocyclyls are
benzoxazol-2-yl, benzthiazol-2-yl and benzimidazol-2-yl. Example
6-membered heterocyclyls contain one to three nitrogen atoms and
optionally a sulfur or oxygen atom, for example pyridyl, such as
pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl; pyrimidyl, such as
pyrimid-2-yl and pyrimid-4-yl; triazinyl, such as
1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl; pyridazinyl, in
particular pyridazin-3-yl, and pyrazinyl. The pyridine N-oxides and
pyridazine N-oxides and the pyridyl, pyrimid-2-yl, pyrimid-4-yl,
pyridazinyl and the 1,3,4-triazin-2-yl groups, are other example
heterocyclyl groups.
As used herein, the term "partially unsaturated" refers to a ring
moiety that includes at least one double or triple bond between
ring atoms but the ring moiety is not aromatic.
As used herein, the term "inhibitor" refers to a compound that
binds to and inhibits a bromodomain with measurable affinity and
activity. In certain embodiments, an inhibitor has an IC.sub.50 or
binding constant of less about 50 .mu.M, less than about 1 .mu.M,
less than about 500 nM, less than about 100 nM, or less than about
10 nM.
The terms "measurable affinity" and "measurably inhibit," as used
herein, refer to a measurable reduction in activity of a
bromodomain between: (i) a sample comprising a compound of formula
I or composition thereof and such bromodomain, and (ii) an
equivalent sample comprising such bromodomain, in the absence of
said compound, or composition thereof.
"Pharmaceutically acceptable salts" include both acid and base
addition salts. It is to be understood that when a compound or
Example herein is shown as a specific salt, the corresponding
free-base, as well as other salts of the corresponding free-base
(including pharmaceutically acceptable salts of the corresponding
free-base) are contemplated.
"Pharmaceutically acceptable acid addition salt" refers to those
salts which retain the biological effectiveness and properties of
the free bases and which are not biologically or otherwise
undesirable, formed with inorganic acids such as hydrochloric acid,
hydrobromic acid, sulfuric acid, nitric acid, carbonic acid,
phosphoric acid and the like, and organic acids may be selected
from aliphatic, cycloaliphatic, aromatic, araliphatic,
heterocyclic, carboxylic, and sulfonic classes of organic acids
such as formic acid, acetic acid, propionic acid, glycolic acid,
gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid,
maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric
acid, citric acid, aspartic acid, ascorbic acid, glutamic acid,
anthranilic acid, benzoic acid, cinnamic acid, mandelic acid,
embonic acid, phenylacetic acid, methanesulfonic acid,
ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,
salicylic acid and the like.
"Pharmaceutically acceptable base addition salts" include those
derived from inorganic bases such as sodium, potassium, lithium,
ammonium, calcium, magnesium, iron, zinc, copper, manganese,
aluminum salts and the like. Particularly base addition salts are
the ammonium, potassium, sodium, calcium and magnesium salts. Salts
derived from pharmaceutically acceptable organic nontoxic bases
includes salts of primary, secondary, and tertiary amines,
substituted amines including naturally occurring substituted
amines, cyclic amines and basic ion exchange resins, such as
isopropylamine, trimethylamine, diethylamine, triethylamine,
tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine,
dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,
hydrabamine, choline, betaine, ethylenediamine, glucosamine,
methylglucamine, theobromine, purines, piperizine, piperidine,
N-ethylpiperidine, polyamine resins and the like. Particular
organic non-toxic bases are isopropylamine, diethylamine,
ethanolamine, tromethamine, dicyclohexylamine, choline, and
caffeine.
The term "tautomer" or "tautomeric form" refers to structural
isomers of different energies which are interconvertible via a low
energy barrier. For example, proton tautomers (also known as
prototropic tautomers) include interconversions via migration of a
proton, such as keto-enol and imine-enamine isomerizations. Valence
tautomers include interconversions by reorganization of some of the
bonding electrons.
A "solvate" refers to an association or complex of one or more
solvent molecules and a compound of the present invention. Examples
of solvents include water, isopropanol, ethanol, methanol, DMSO,
ethyl acetate, acetic acid and ethanolamine. The term "hydrate"
refers to the complex where the solvent molecule is water.
"Therapeutically effective amount" refers to an amount of a
compound of the present invention that (i) treats the particular
disease, condition or disorder, (ii) attenuates, ameliorates or
eliminates one or more symptoms of the particular disease,
condition, or disorder, or (iii) prevents or delays the onset of
one or more symptoms of the particular disease, condition or
disorder described herein. In the case of cancer, the
therapeutically effective amount of the drug may reduce the number
of cancer cells; reduce the tumor size; inhibit (i.e., slow to some
extent and preferably stop) cancer cell infiltration into
peripheral organs; inhibit (i.e., slow to some extent and
preferably stop) tumor metastasis; inhibit, to some extent, tumor
growth; and/or relieve to some extent one or more of the symptoms
associated with the cancer. For cancer therapy, efficacy can, for
example, be measured by assessing the time to disease progression
(TTP) and/or determining the response rate (RR).
In the case of immunological disorders, the therapeutic effective
amount is an amount sufficient to decrease or alleviate an allergic
disorder, the symptoms of an autoimmune and/or inflammatory
disease, or the symptoms of an acute inflammatory reaction (e.g.
asthma). In some embodiments, a therapeutically effective amount is
an amount of a chemical entity described herein sufficient to
significantly decrease the activity or number of drug tolerant or
drug tolerant persisting cancer cells.
"Treatment" (and variations such as "treat" or "treating") refers
to clinical intervention in an attempt to alter the natural course
of the individual or cell being treated, and can be performed
either for prophylaxis or during the course of clinical
pathology.
Desirable effects of treatment include one or more of preventing
occurrence or recurrence of disease, alleviation of symptoms,
diminishment of any direct or indirect pathological consequences of
the disease, stabilized (i.e., not worsening) state of disease,
preventing metastasis, decreasing the rate of disease progression,
amelioration or palliation of the disease state, prolonging
survival as compared to expected survival if not receiving
treatment and remission or improved prognosis. In certain
embodiments, a compound of formula I is used to delay development
of a disease or disorder or to slow the progression of a disease or
disorder. Those individuals in need of treatment include those
already with the condition or disorder as well as those prone to
have the condition or disorder, (for example, through a genetic
mutation or aberrant expression of a gene or protein) or those in
which the condition or disorder is to be prevented.
As used herein, "a" or "an" means one or more, unless clearly
indicated otherwise.
As used herein, "another" means at least a second or more.
Exemplary Values
One embodiment provides a compound of formula (I) or a salt
thereof, wherein:
R.sup.1 is methyl, ethyl, C.sub.3-12alkyl, C.sub.2-12alkenyl,
C.sub.2-12alkynyl, carbocyclyl, or heterocyclyl, wherein any methyl
of R.sup.1 is substituted with one or more groups R.sup.m, wherein
any ethyl of R.sup.1 is substituted with one or more groups
R.sup.n, and wherein any C.sub.3-12alkyl, C.sub.2-12alkenyl,
C.sub.2-12alkynyl, carbocyclyl or heterocyclyl of R.sup.1 is
optionally substituted with one or more groups R.sup.a;
R.sup.2 is H, C.sub.1-12alkyl, C.sub.2-12alkenyl,
C.sub.2-12alkynyl, or C.sub.3-8cycloalkyl, wherein each
C.sub.1-12alkyl, C.sub.2-12alkenyl, C.sub.2-12alkynyl, or
C.sub.3-8cycloalkyl of R.sup.2 is optionally substituted with one
or more groups R.sup.b;
Q is carbocyclyl or heterocyclyl, which carbocyclyl or heterocyclyl
is optionally substituted with one or more groups R.sup.c;
each R.sup.a is independently selected from oxo, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6haloalkyl,
carbocyclyl, heterocyclyl, --F, --Cl, --Br, --I, --NO.sub.2,
--N(R.sup.v).sub.2, --CN, --C(O)--N(R.sup.v).sub.2,
--S(O)--N(R.sup.v).sub.2, --S(O).sub.2--N(R.sup.v).sub.2,
--O--R.sup.v, --S--R.sup.v, --O--C(O)--R.sup.v,
--O--C(O)--O--R.sup.v, --C(O)--R.sup.v, --C(O)--O--R.sup.v,
--S(O)--R.sup.v, --S(O).sub.2--R.sup.v,
--O--C(O)--N(R.sup.v).sub.2, --N(R.sup.v)--C(O)--OR.sup.v,
--N(R.sup.v)--C(O)--N(R.sup.v).sub.2, --N(R.sup.v)--C(O)--R.sup.v,
--N(R.sup.v)--S(O)--R.sup.v, --N(R.sup.v)--S(O).sub.2--R.sup.v,
--N(R.sup.v)--S(O)--N(R.sup.v).sub.2, and
--N(R.sup.v)--S(O).sub.2--N(R.sup.v).sub.2;
each R.sup.b is independently selected from oxo, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6haloalkyl,
carbocyclyl, heterocyclyl, --F, --Cl, --Br, --I, --NO.sub.2,
--N(R.sup.w).sub.2, --CN, --C(O)--N(R.sup.w).sub.2,
--S(O)--N(R.sup.w).sub.2, --S(O).sub.2--N(R.sup.w).sub.2,
--O--R.sup.w, --S--R.sup.w, --O--C(O)--R.sup.w,
--O--C(O)--O--R.sup.w, --C(O)--R.sup.w, --C(O)--O--R.sup.w,
--S(O)--R.sup.w, --S(O).sub.2--R.sup.w,
--O--C(O)--N(R.sup.w).sub.2, --N(R.sup.w)--C(O)--OR.sup.w,
--N(R.sup.w)--C(O)--N(R.sup.w).sub.2, --N(R.sup.w)--C(O)--R.sup.w,
--N(R.sup.w)--S(O)--R.sup.w, --N(R.sup.w)--S(O).sub.2--R.sup.w,
--N(R.sup.w)--S(O)--N(R.sup.w).sub.2, and
--N(R.sup.w)--S(O).sub.2--N(R.sup.w).sub.2, wherein any
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6haloalkyl, carbocyclyl, or heterocyclyl is optionally
substituted with one or more groups independently selected from
oxo, halo, --NO.sub.2, --N(R.sup.w).sub.2, --CN,
--C(O)--N(R.sup.w).sub.2, --S(O)--N(R.sup.w).sub.2,
--S(O).sub.2--N(R.sup.w).sub.2, --O--R.sup.w, --S--R.sup.w,
--O--C(O)--R.sup.w, --C(O)--R.sup.w, --C(O)--O--R.sup.w,
--S(O)--R.sup.w, --S(O).sub.2--R.sup.w, --C(O)--N(R.sup.w).sub.2,
--N(R.sup.w)--C(O)--R.sup.w, --N(R.sup.w)--S(O)--R.sup.w,
--N(R.sup.w)--S(O).sub.2--R and C.sub.1-4alkyl that is optionally
substituted with one or more groups independently selected from oxo
and halo;
each R.sup.c is independently selected from oxo, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6haloalkyl,
carbocyclyl, heterocyclyl, --F, --Cl, --Br, --I, --NO.sub.2,
--N(R.sup.u).sub.2, --CN, --C(O)--N(R.sup.u).sub.2,
--S(O)--N(R.sup.u).sub.2, --S(O).sub.2--N(R.sup.u).sub.2,
--O--R.sup.u, --S--R.sup.u, --O--C(O)--R.sup.u,
--O--C(O)--O--R.sup.u, --C(O)--R.sup.u, --C(O)--O--R.sup.u,
--S(O)--R.sup.u, --S(O).sub.2--R.sup.u,
--O--C(O)--N(R.sup.u).sub.2, --N(R.sup.u)--C(O)--OR.sup.u,
--N(R.sup.u)--C(O)--N(R.sup.u).sub.2, --N(R.sup.u)--C(O)--R.sup.u,
--N(R.sup.u)--S(O)--R.sup.u, --N(R.sup.u)--S(O).sub.2--R.sup.u,
--N(R.sup.u)--S(O)--N(R.sup.u).sub.2, and
--N(R.sup.u)--S(O).sub.2--N(R.sup.u).sub.2, wherein any
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6haloalkyl, carbocyclyl, or heterocyclyl is optionally
substituted with one or more groups independently selected from
oxo, halo, --NO.sub.2, --N(R.sup.u).sub.2, --CN,
--C(O)--N(R.sup.u).sub.2, --S(O)--N(R.sup.u).sub.2,
--S(O).sub.2--N(R.sup.u).sub.2, --O--R.sup.u, --S--R.sup.u,
--O--C(O)--R.sup.u, --C(O)--R.sup.u, --C(O)--O--R.sup.u,
--S(O)--R.sup.u, --S(O).sub.2--R.sup.u,
--N(R.sup.u)--C(O)--R.sup.u, --N(R.sup.u)--S(O)--R.sup.u,
--N(R.sup.u)--S(O).sub.2--R.sup.u and C.sub.1-4alkyl that is
optionally substituted with one or more groups independently
selected from oxo and halo;
each R.sup.m is independently selected from oxo, carbocyclyl,
heterocyclyl, --F, --NO.sub.2, --CN, --C(O)--N(R.sup.v).sub.2,
--S(O)--N(R.sup.u).sub.2, --S(O).sub.2--N(R.sup.v).sub.2,
--C(O)--R.sup.v, --C(O)--O--R.sup.v, --S(O)--R.sup.v, and
--S(O).sub.2--R.sup.v, wherein carbocyclyl is optionally
substituted with one or more --O--R.sup.v;
each R.sup.n is independently selected from oxo, carbocyclyl,
heterocyclyl, --F, --Cl, --Br, --I, --NO.sub.2, --N(R.sup.v).sub.2,
--CN, --C(O)--N(R.sup.v).sub.2, --S(O)--N(R.sup.v).sub.2,
--S(O).sub.2--N(R.sup.v).sub.2, --O--R.sup.v, --S--R.sup.v,
--O--C(O)--R.sup.v, --O--C(O)--O--R.sup.v, --C(O)--R.sup.v,
--C(O)--O--R.sup.v, --S(O)--R.sup.v, --S(O).sub.2--R.sup.v,
--O--C(O)--N(R.sup.v).sub.2, --N(R.sup.v)--C(O)--OR.sup.v,
--N(R.sup.v)--C(O)--N(R.sup.v).sub.2, --N(R.sup.v)--C(O)--R.sup.v,
--N(R.sup.v)--S(O)--R.sup.v, --N(R.sup.v)--S(O).sub.2--R.sup.v,
--N(R.sup.v)--S(O)--N(R.sup.v).sub.2, and
--N(R.sup.v)--S(O).sub.2--N(R.sup.v).sub.2;
each R.sup.u is independently selected from hydrogen,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, carbocyclyl,
and heterocyclyl, wherein each C.sub.1-4alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, carbocyclyl, or heterocyclyl is optionally
substituted with one or more groups independently selected from
oxo, halo, --N(R.sup.ua).sub.2, hydroxyl, carbocyclyl,
heterocyclyl, and C.sub.1-C.sub.6 alkyl that is optionally
substituted with one or more groups independently selected from oxo
and halo; or two R.sup.u are taken together with the nitrogen to
which they are attached to form a heterocyclyl that is optionally
substituted with one or more groups independently selected from
oxo, halo, C.sub.1-3alkyl and heteroaryl wherein C.sub.1-3alkyl is
optionally substituted with one or more groups independently
selected from oxo, hydroxyl, --N(R.sup.ua).sub.2 and halo and
heteroaryl is optionally substituted with one or more
--N(R.sup.ua).sub.2;
each R.sup.v is independently selected from hydrogen,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, carbocyclyl,
and heterocyclyl, wherein each C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, carbocyclyl, or heterocyclyl is optionally
substituted with one or more groups independently selected from
oxo, halo, --N(R.sup.va).sub.2, hydroxyl, carbocyclyl,
heterocyclyl, and C.sub.1-C.sub.6 alkyl that is optionally
substituted with one or more groups independently selected from oxo
and halo; or two R are taken together with the nitrogen to which
they are attached to form a heterocyclyl that is optionally
substituted with one or more groups independently selected from
oxo, halo and C.sub.1-3alkyl that is optionally substituted with
one or more groups independently selected from oxo and halo;
each R.sup.w is independently selected from hydrogen,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, carbocyclyl,
and heterocyclyl, wherein each C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, carbocyclyl, or heterocyclyl is optionally
substituted with one or more groups independently selected from
oxo, halo, --N(R.sup.wa).sub.2, hydroxyl, and C.sub.1-C.sub.6 alkyl
that is optionally substituted with one or more groups
independently selected from oxo and halo; or two R.sup.w are taken
together with the nitrogen to which they are attached to form a
heterocyclyl that is optionally substituted with one or more groups
independently selected from oxo, halo and C.sub.1-3alkyl that is
optionally substituted with one or more groups independently
selected from oxo and halo;
each R.sup.ua is independently selected from hydrogen and
C.sub.1-6alkyl;
each R.sup.va is independently selected from hydrogen and
C.sub.1-6alkyl; and
each R.sup.wa is independently selected from hydrogen and
C.sub.1-6alkyl.
One embodiment provides a compound of formula (I) or a salt
thereof, wherein
R.sup.1 is methyl, ethyl, C.sub.3-12alkyl, C.sub.2-12alkenyl,
C.sub.2-12alkynyl, carbocyclyl, or heterocyclyl, wherein any methyl
of R.sup.1 is substituted with one or more groups R.sup.m, wherein
any ethyl of R.sup.1 is substituted with one or more groups
R.sup.n, and wherein any C.sub.3-12alkyl, C.sub.2-12alkenyl,
C.sub.2-12alkynyl, carbocyclyl or heterocyclyl of R.sup.1 is
optionally substituted with one or more groups R.sup.a;
R.sup.2 is H, C.sub.1-12alkyl, C.sub.2-12alkenyl,
C.sub.2-12alkynyl, or C.sub.3-8cycloalkyl, wherein each
C.sub.1-12alkyl, C.sub.2-12alkenyl, C.sub.2-12alkynyl, or
C.sub.3-8cycloalkyl of R.sup.2 is optionally substituted with one
or more groups R.sup.b;
Q is carbocyclyl or heterocyclyl, which carbocyclyl or heterocyclyl
is optionally substituted with one or more groups R.sup.c;
each R.sup.a is independently selected from oxo, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6haloalkyl,
carbocyclyl, heterocyclyl, --F, --Cl, --Br, --I, --NO.sub.2,
--N(R.sup.v).sub.2, --CN, --C(O)--N(R.sup.v).sub.2,
--S(O)--N(R.sup.v).sub.2, --S(O).sub.2--N(R.sup.v).sub.2,
--O--C(O)--R.sup.v, --O--C(O)--O--R.sup.v, --C(O)--R.sup.v,
--C(O)--O--R.sup.v, --S(O)--R.sup.v, --S(O).sub.2--R.sup.v,
--O--C(O)--N(R.sup.v).sub.2, --N(R.sup.v)--C(O)--OR.sup.v,
--N(R.sup.v)--C(O)--N(R.sup.v).sub.2, C(O)--R.sup.v,
--N(R.sup.v)--S(O)--R.sup.v, --N(R.sup.v)--S(O).sub.2--R.sup.v,
--N(R.sup.v)--S(O)--N(R.sup.v).sub.2, and
--N(R.sup.v)--S(O).sub.2--N(R.sup.v).sub.2;
each R.sup.b is independently selected from oxo, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6 haloalkyl,
carbocyclyl, heterocyclyl, --F, --Cl, --Br, --I, --NO.sub.2,
--N(R.sup.w).sub.2, --CN, --C(O)--N(R.sup.w).sub.2,
--S(O)--N(R.sup.w).sub.2, --S(O).sub.2--N(e).sub.2,
--O--C(O)--R.sup.w, --O--C(O)--O--R.sup.w, --C(O)--R.sup.w,
--C(O)--O--R.sup.w, --S(O)--R.sup.w, --S(O).sub.2--R.sup.w,
--O--C(O)--N(R.sup.w).sub.2, --N(R.sup.w)--C(O)--OR.sup.w,
--N(R.sup.w)--C(O)--N(R.sup.w).sub.2, --N(R.sup.w)--C(O)--R.sup.w,
--N(R.sup.w)--S(O)--R.sup.w, --N(R.sup.w)--S(O).sub.2--R.sup.w,
--N(R.sup.w)--S(O)--N(R.sup.w).sub.2, and
--N(R.sup.w)--S(O).sub.2--N(R.sup.w).sub.2, wherein any
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6haloalkyl, carbocyclyl, or heterocyclyl is optionally
substituted with one or more groups independently selected from
oxo, halo, --NO.sub.2, --N(R.sup.w).sub.2, --CN,
--C(O)--N(R.sup.w).sub.2, --S(O)--N(R.sup.w).sub.2,
--S(O).sub.2--N(R.sup.w).sub.2, --O--C(O)--R.sup.w,
--C(O)--O--R.sup.w, --S(O)--R.sup.w, --S(O).sub.2--R.sup.w,
--C(O)--N(R.sup.w).sub.2, --N(R.sup.w)--S(O).sub.2--R.sup.w and
C.sub.1-6alkyl that is optionally substituted with one or more
groups independently selected from oxo and halo;
each R.sup.c is independently selected from oxo, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6haloalkyl,
carbocyclyl, heterocyclyl, --F, --Cl, --Br, --I, --NO.sub.2,
--N(R.sup.u).sub.2, --CN, --C(O)--N(R.sup.u).sub.2,
--S(O)--N(R.sup.u).sub.2, --S(O).sub.2--N(R.sup.u).sub.2,
--S--R.sup.u, --O--C(O)--R.sup.u, --O--C(O)--O--R.sup.u,
--C(O)--R.sup.u, --C(O)--O--R.sup.u, --S(O)--R.sup.u,
--S(O).sub.2--R.sup.u, --O--C(O)--N(R.sup.u).sub.2,
--N(R.sup.u)--C(O)--OR.sup.u, --N(R.sup.u)--C(O)--N(R.sup.u).sub.2,
--N(R.sup.u)--C(O)--R.sup.u, --N(R.sup.u)--S(O)--R.sup.u,
--N(R.sup.u)--S(O).sub.2--R.sup.u,
--N(R.sup.u)--S(O)--N(R.sup.u).sub.2, and
--N(R.sup.u)--S(O).sub.2--N(R.sup.u).sub.2, wherein any
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6haloalkyl, carbocyclyl, or heterocyclyl is optionally
substituted with one or more groups independently selected from
oxo, halo, --NO.sub.2, --N(R.sup.u).sub.2, --CN,
--C(O)--N(R.sup.u).sub.2, --S(O)--N(R.sup.u).sub.2,
--S(O).sub.2--N(R.sup.u).sub.2, --O--R.sup.u, --O--C(O)--R.sup.u,
--C(O)--R.sup.u, --C(O)--O--R.sup.u, --S(O)--R.sup.u,
--S(O).sub.2--R.sup.u, --C(O)--N(R.sup.u).sub.2,
--N(R.sup.u)--C(O)--R.sup.u, --N(R.sup.u)--S(O)--R.sup.u,
--N(R.sup.u)--S(O).sub.2--R.sup.u and C.sub.1-6alkyl that is
optionally substituted with one or more groups independently
selected from oxo and halo;
each R.sup.m is independently selected from oxo, carbocyclyl,
heterocyclyl, --F, --NO.sub.2, --CN, --C(O)--N(R.sup.v).sub.2,
--S(O)--N(R.sup.v).sub.2, --S(O).sub.2--N(R.sup.v).sub.2,
--C(O)--R.sup.v, --C(O)--O--R.sup.v, --S(O)--R.sup.v, and
--S(O).sub.2--R.sup.v;
each R.sup.n is independently selected from oxo, carbocyclyl,
heterocyclyl, --F, --Cl, --Br, --I, --NO.sub.2, --N(R.sup.v).sub.2,
--CN, --C(O)--N(R.sup.v).sub.2, --S(O)--N(R.sup.v).sub.2,
--S(O).sub.2--N(R.sup.v).sub.2, --S--R.sup.v, --O--C(O)--R.sup.v,
--O--C(O)--O--R.sup.v, --C(O)--R.sup.v, --C(O)--O--R.sup.v,
--S(O)--R.sup.v, --S(O).sub.2--R.sup.v,
--O--C(O)--N(R.sup.v).sub.2,
--N(R.sup.v)--C(O)--N(R.sup.v)--C(O)--N(R.sup.v).sub.2,
--N(R.sup.v)--C(O)--R.sup.v, --N(R.sup.v)--S(O)--R.sup.v,
--N(R.sup.v)--S(O).sub.2--R.sup.v, --N(Fe)--S(O)--N(R.sup.v).sub.2,
and --N(R.sup.v)--S(O).sub.2--N(R.sup.v).sub.2;
each R.sup.u is independently selected from hydrogen,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, carbocyclyl,
and heterocyclyl, wherein each C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, carbocyclyl, or heterocyclyl is optionally
substituted with one or more groups independently selected from
oxo, halo, --N(R.sup.ua).sub.2, hydroxyl, carbocyclyl,
heterocyclyl, and C.sub.1-C.sub.6 alkyl that is optionally
substituted with one or more groups independently selected from oxo
and halo; or two R.sup.u are taken together with the nitrogen to
which they are attached to form a heterocyclyl that is optionally
substituted with one or more groups independently selected from
oxo, halo and C.sub.1-3alkyl that is optionally substituted with
one or more groups independently selected from oxo and halo;
each R.sup.v is independently selected from hydrogen,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, carbocyclyl,
and heterocyclyl, wherein each C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, carbocyclyl, or heterocyclyl is optionally
substituted with one or more groups independently selected from
oxo, halo, --N(R.sup.va).sub.2, hydroxyl, carbocyclyl,
heterocyclyl, and C.sub.1-C.sub.6 alkyl that is optionally
substituted with one or more groups independently selected from oxo
and halo; or two R.sup.v are taken together with the nitrogen to
which they are attached to form a heterocyclyl that is optionally
substituted with one or more groups independently selected from
oxo, halo and C.sub.1-3alkyl that is optionally substituted with
one or more groups independently selected from oxo and halo;
each R.sup.w is independently selected from hydrogen,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, carbocyclyl,
and heterocyclyl, wherein each C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6 alkynyl, carbocyclyl, or heterocyclyl is optionally
substituted with one or more groups independently selected from
oxo, halo, --N(R.sup.wa).sub.2, hydroxyl, and C.sub.1-C.sub.6 alkyl
that is optionally substituted with one or more groups
independently selected from oxo and halo; or two R.sup.w are taken
together with the nitrogen to which they are attached to form a
heterocyclyl that is optionally substituted with one or more groups
independently selected from oxo, halo and C.sub.1-3alkyl that is
optionally substituted with one or more groups independently
selected from oxo and halo;
each R.sup.ua is independently selected from hydrogen and
C.sub.1-6alkyl;
each R.sup.ya is independently selected from hydrogen and
C.sub.1-6alkyl; and
each R.sup.wa is independently selected from hydrogen and
C.sub.1-6alkyl.
With respect to the embodiments for formula (I) noted above, the
following exemplary values are provided. It is to be understood
that two or more embodiments provided herein may be combined.
In certain embodiments R.sup.1 is methyl that is substituted with
one or more groups R.sup.m.
In certain embodiments R.sup.1 is ethyl that is substituted with
one or more groups R.sup.n.
In certain embodiments R.sup.1 is C.sub.3-12alkyl,
C.sub.2-12alkenyl, C.sub.2-12alkynyl, carbocyclyl or heterocyclyl,
wherein any C.sub.3-12alkyl, C.sub.2-12alkenyl, C.sub.2-12alkynyl,
carbocyclyl or heterocyclyl of R.sup.1 is optionally substituted
with one or more groups R.sup.a.
In certain embodiments R.sup.1 is C.sub.3-6alkyl or
C.sub.3-6alkenyl, wherein each C.sub.3-6alkyl and C.sub.3-6alkenyl
is optionally substituted with one or more groups independently
selected from carbocyclyl, heterocyclyl, --F, --Cl, --Br, --I,
--N(R.sup.v).sub.2, --CN, --C(O)--N(R.sup.v).sub.2, --O--R.sup.v,
--O--C(O)--R.sup.v, --C(O)--R.sup.v, and --C(O)--O--R.sup.v.
In certain embodiments R.sup.1 is C.sub.3-6alkyl or
C.sub.3-6alkenyl, wherein each C.sub.3-6alkyl and C.sub.3-6alkenyl
is optionally substituted with one or more groups independently
selected from carbocyclyl, --F, --Cl, --O--R.sup.v,
--O--C(O)--R.sup.v, --C(O)--R.sup.v, and --C(O)--O--R.sup.v.
In certain embodiments R.sup.1 is C.sub.3-6alkyl or
C.sub.3-6alkenyl, wherein each C.sub.3-6alkyl and C.sub.3-6alkenyl
is optionally substituted with one or more groups independently
selected from C.sub.3-6cycloalkyl.
In certain embodiments R.sup.1 is butyl, 2-cyclopropylethyl,
cyclopentylmethyl, 2-penten-1-yl, cyclohexylmethyl,
cyclobutylmethyl, 2-cyclohexylethyl, pentyl, 2-methylpropyl,
2-buten-1-yl, butyl, 2-furylmethyl, 3-methylbut-1-yl, 2-propenyl,
3-methyl-2-buten-1-yl, 3-buten-1-yl, 2-methoxyethyl,
3-methoxypropyl, or 4-methoxybenzyl.
In certain embodiments R.sup.2 is H.
In certain embodiments R.sup.2 is C.sub.1-12alkyl that is
optionally substituted with one or more groups R.sup.b.
In certain embodiments R.sup.2 is methyl.
In certain embodiments R.sup.2 is H or C.sub.1-12alkyl that is
optionally substituted with one or more groups R.sup.b.
In certain embodiments R.sup.2 is H or C.sub.1-6alkyl that is
optionally substituted with one or more groups R.sup.b.
In certain embodiments R.sup.2 is H or C.sub.1-6alkyl that is
optionally substituted with one or more groups R.sup.b.
In certain embodiments R.sup.2 is H or C.sub.1-6alkyl.
In certain embodiments R.sup.2 is H or C.sub.1-4alkyl.
In certain embodiments R.sup.2 is H or methyl.
In certain embodiments Q is carbocyclyl or heterocyclyl, which
carbocyclyl or heterocyclyl is optionally substituted with one or
more groups R.sup.c.
In certain embodiments Q is carbocyclyl that is optionally
substituted with one or more groups R.sup.c.
In certain embodiments Q is heterocyclyl that is optionally
substituted with one or more groups R.sup.c.
In certain embodiments Q is C.sub.3-C.sub.8cycloalkyl that is
optionally substituted with one or more groups R.sup.c.
In certain embodiments Q is aryl that is optionally substituted
with one or more groups R.sup.c.
In certain embodiments Q is phenyl that is optionally substituted
with one or more groups R.sup.c.
In certain embodiments Q is:
##STR00003## wherein:
ring A is optionally substituted with one or more groups R.sup.g,
or ring A is optionally fused with a carbocyclyl or a heterocyclyl
to form a polycyclyl that is optionally substituted with one or
more groups R.sup.g;
R.sup.e is hydrogen, --F, --Cl, --Br, --CN, C.sub.1-6alkyl,
C.sub.2-6alkenyl, or C.sub.2-6alkynyl, wherein each C.sub.1-6alkyl,
C.sub.2-6alkenyl, or C.sub.2-6alkynyl is optionally substituted
with one or more groups independently selected from oxo, --F, --Br,
--I, --NO.sub.2, --N(R.sup.x).sub.2, --CN,
--C(O)--N(R.sup.x).sub.2, --S(O)--N(R.sup.x).sub.2,
--S(O).sub.2--N(R.sup.x).sub.2, --S--R.sup.x, --O--C(O)--R.sup.x,
--C(O)--R.sup.x, --C(O)--O--R.sup.x, --S(O)--R.sup.x,
--S(O).sub.2--R.sup.x, --O--C(O)--N(R.sup.x).sub.2,
--N(R.sup.x)--C(O)--OR.sup.x,
--N(R.sup.x)--C(O)--N(R.sup.x).sub.2--N(R.sup.x)--C(O)--R.sup.x,
--N(R.sup.x)--S(O)--R.sup.x, --N(R.sup.x)--S(O).sub.2--R.sup.x,
--N(R.sup.x)--S(O)--N(R.sup.x).sub.2, and
--N(R.sup.x)--S(O).sub.2--N(R.sup.x).sub.2;
R.sup.f is hydrogen, --F, --Cl, --Br, --I, --CN, --O--R.sup.y,
C.sub.1-6alkyl, C.sub.2-6alkenyl, or C.sub.2-6alkynyl, wherein each
C.sub.1-6alkyl, C.sub.2-6alkenyl, or C.sub.2-6alkynyl is optionally
substituted with one or more groups independently selected from
oxo, --F, --Cl, --Br, --I, --NO.sub.2, --N(R.sup.y).sub.2, --CN,
--C(O)--N(R.sup.y).sub.2, --S(O)--N(R.sup.y).sub.2,
--S(O).sub.2--N(R.sup.y).sub.2, --O--R.sup.y, --S--R.sup.y,
--O--C(O)--R.sup.y, --C(O)--R.sup.y, --C(O)--O--R.sup.y,
--S(O)--R.sup.y, --S(O).sub.2--R.sup.y,
--O--C(O)--N(R.sup.y).sub.2, --N(R.sup.y)--C(O)--OR.sup.y,
--N(R.sup.y)--C(O)--N(R.sup.y).sub.2, --N(R.sup.y)--C(O)--R.sup.y,
--N(R.sup.y)--S(O)--R.sup.y, --N(R.sup.y)--S(O).sub.2--R.sup.y,
--N(R.sup.y)--S(O)--N(R.sup.y).sub.2, and
--N(R.sup.y)--S(O).sub.2--N(R.sup.y).sub.2;
each R.sup.g is independently selected from oxo, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6 haloalkyl,
carbocyclyl, heterocyclyl, --F, --Cl, --Br, --I, --NO.sub.2,
--N(R.sup.x).sub.2, --CN, --C(O)--N(R.sup.z).sub.2,
--S(O)--N(R.sup.z).sub.2, --S(O).sub.2--N(R.sup.z).sub.2,
--S--R.sup.z, --O--C(O)--R.sup.z, --O--C(O)--O--R.sup.z,
--C(O)--R.sup.z, --C(O)--O--R.sup.z, --S(O)--R.sup.z,
--S(O).sub.2--R.sup.z, --O--C(O)--N(R.sup.z).sub.2,
--N(R.sup.z)--C(O)--OR.sup.z, --N(R.sup.z)--C(O)--N(R.sup.z).sub.2,
--N(R.sup.z)--C(O)--R.sup.z, --N(R.sup.z)--S(O)--R.sup.z,
--N(R.sup.z)--S(O).sub.2--R.sup.z,
--N(R.sup.z)--S(O)--N(R.sup.z).sub.2, and
--N(R.sup.z)--S(O).sub.2--N(R.sup.z).sub.2, wherein any
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6haloalkyl, carbocyclyl, or heterocyclyl is optionally
substituted with one or more groups independently selected from
oxo, halo, --NO.sub.2, --N(R.sup.z).sub.2, --CN,
--C(O)--N(R.sup.z).sub.2, --S(O)--N(R.sup.z).sub.2,
--S(O).sub.2--N(R.sup.z).sub.2, --S--R.sup.z, --O--C(O)--R.sup.z,
--C(O)--R.sup.z, --C(O)--O--R.sup.z, --S(O)--R.sup.z,
--S(O).sub.2--R.sup.z, --C(O)--N(R.sup.z).sub.2,
--N(R.sup.z)--C(O)--R.sup.z, --N(R.sup.z)--S(O)--R.sup.z,
--N(R.sup.z)--S(O).sub.2--R.sup.z, C.sub.1-6alkyl that is
optionally substituted with one or more groups independently
selected from oxo and halo, and heterocyclyl that is optionally
substituted with one or more groups independently selected from
oxo, halo, and C.sub.1-6alkyl;
each R.sup.x is independently selected from hydrogen,
C.sub.1-6alkyl, C.sub.2-6alkenyl, and C.sub.2-6alkynyl, wherein
each C.sub.1-6alkyl, C.sub.2-6alkenyl, or C.sub.2-6alkynyl is
optionally substituted with one or more groups independently
selected from oxo, halo, amino, hydroxyl, and C.sub.1-C.sub.6
alkyl;
each R.sup.y is independently selected from hydrogen,
C.sub.1-6alkyl, C.sub.2-6alkenyl, and C.sub.2-6alkynyl, wherein
each C.sub.1-6alkyl, C.sub.2-6alkenyl, or C.sub.2-6alkynyl is
optionally substituted with one or more groups independently
selected from oxo, halo, amino, hydroxyl, and C.sub.1-C.sub.6
alkyl; and
each R.sup.z is independently selected from hydrogen,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, carbocyclyl,
and heterocyclyl, wherein each C.sub.1-6alkyl, C.sub.2 alkenyl,
C.sub.2-6alkynyl, carbocyclyl, or heterocyclyl is optionally
substituted with one or more groups independently selected from
oxo, halo, cyano, amino, hydroxyl, C.sub.1-C.sub.6alkoxy,
carbocyclyl, and C.sub.1-C.sub.6 alkyl that is optionally
substituted with one or more groups independently selected from oxo
and halo; or two R.sup.z are taken together with the nitrogen to
which they are attached to form a heterocyclyl that is optionally
substituted with one or more groups independently selected from
oxo, halo and C.sub.1-3alkyl that is optionally substituted with
one or more groups independently selected from oxo and halo.
In certain embodiments R.sup.e is hydrogen.
In certain embodiments R.sup.f is hydrogen.
In certain embodiments ring A is optionally substituted with one or
more groups R.sup.g.
In certain embodiments Q is C.sub.3-C.sub.8heterocycloalkyl that is
optionally substituted with one or more groups R.sup.c.
In certain embodiments Q is heteroaryl that is optionally
substituted with one or more groups R.sup.c.
In certain embodiments Q is phenyl that is optionally substituted
with one or more groups R.sup.c, wherein each R.sup.c is
independently selected from C.sub.1-6alkyl, heterocyclyl, --F,
--Cl, --CN, --C(O)--N(R.sup.u).sub.2, and --O--R.sup.u, wherein any
C.sub.1-6alkyl or heterocyclyl is optionally substituted with one
or more groups independently selected from oxo, halo, --NO.sub.2,
--N(R.sup.u).sub.2, --CN, --C(O)--N(R.sup.u).sub.2,
--S(O)--N(R.sup.u).sub.2, --S(O).sub.2--N(R.sup.u).sub.2,
--O--R.sup.u, --S--R.sup.u, --O--C(O)--R.sup.u, --C(O)--R.sup.u,
--C(O)--O--R.sup.u, --S(O)--R.sup.u, --S(O).sub.2--R.sup.u,
--C(O)--N(R.sup.u).sub.2, --N(R.sup.u)--C(O)--R.sup.u,
--N(R.sup.u)--S(O)--R.sup.u, --N(R.sup.u)--S(O).sub.2--R.sup.u and
C.sub.1-6alkyl that is optionally substituted with one or more
groups independently selected from oxo and halo.
In certain embodiments Q is phenyl that is optionally substituted
with one or more groups R.sup.c, wherein each R.sup.c is
independently selected from C.sub.1-6alkyl, heterocyclyl, --F,
--Cl, --CN, --C(O)--N(R.sup.u).sub.2, and --O--R.sup.u, wherein any
C.sub.1-6alkyl or heterocyclyl is optionally substituted with one
or more groups independently selected from --O--R.sup.u and
C.sub.1-6alkyl that is optionally substituted with one or more
groups independently selected from oxo and halo.
In certain embodiments Q is phenyl that is optionally substituted
with one group --C(O)--N(R.sup.u).sub.2 and is optionally
substituted with one or more groups R.sup.c.
In certain embodiments Q is phenyl that is substituted with a group
--C(O)--N(R.sup.u).sub.2, and that is optionally substituted with
one or more groups R.sup.c, wherein each R.sup.c is independently
selected from C.sub.1-6alkyl, heterocyclyl, --F, --Cl, --CN,
--C(O)--N(R.sup.u).sub.2, and --O--R.sup.u, wherein any
C.sub.1-6alkyl or heterocyclyl is optionally substituted with one
or more groups independently selected from --O--R.sup.u and
C.sub.1-6alkyl that is optionally substituted with one or more
groups independently selected from oxo and halo.
In certain embodiments Q is phenyl that is optionally substituted
with one or more groups R.sup.c, and that is substituted with a
group --C(O)--N(R.sup.u).sub.2 selected from dimethylaminocarbonyl,
aminocarbonyl, cyclohexylaminocarbonyl, isopropylaminocarbonyl,
tetrahydrofuranylaminocarbonyl,
N-(2,2-difluoroethyl)-aminocarbonyl, cyclobutylaminocarbonyl,
cyclopropylmethyl aminocarbonyl, methylaminocarbonyl,
pyrrolidin-1-ylcarbonyl, morpholinocarbonyl, ethylaminocarbonyl,
2-methylpropyl)aminocarbonyl, 2-(dimethylamino)ethylaminocarbonyl,
2-hydroxyethylaminocarbonyl, 1-propylaminocarbonyl,
6-acetyl-2,6-diazaspiro[3.3]heptane-2-ylcarbonyl,
4-methylpiperazin-1-ylcarbonyl, and azetidine-1-carbonyl.
In certain embodiments Q is selected from:
3-((N-dimethylaminocarbonyl)phenyl, 4-aminocarbonyl-3-fluorophenyl,
3-aminocarbonyl-5-fluorophenyl, 4-tert-butylphenyl,
3-(N-cyclohexylaminocarbonyl)phenyl,
4-(N-cyclohexylaminocarbonyl)phenyl,
3-(N-isopropylaminocarbonyl)phenyl, 3-cyano-6-methoxyphenyl,
3-aminocarbonyl-2-fluorophenyl, 3-aminocarbonyl-6-fluorophenyl,
phenyl, 3-(N-cyclohexylaminocarbonyl)-6-methoxyphenyl,
3-(N-tetrahydrofuranylaminocarbonyl)-6-methoxyphenyl,
3-(N-(2,2-difluoroethyl)aminocarbonyl)-6-methoxyphenyl,
3-(N-cyclobutylaminocarbonyl)-6-methoxyphenyl,
3-(N-(cyclopropylmethyl)aminocarbonyl)-6-methoxyphenyl,
4-methyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2-one-7-yl,
3-(N,N-dimethylaminocarbonyl)-5-fluorophenyl,
4-(N-methylaminocarbonyl)phenyl, 3-(pyrrolidin-1-ylcarbonyl)phenyl,
3-aminocarbonylphenyl, 4-(methylsulfonlyamino)phenyl,
4-(morpholinocarbonyl)phenyl,
3-(N,N-dimethylaminocarbonyl)-6-fluorophenyl,
3-(N,N-dimethylaminocarbonyl)-2-fluorophenyl,
3-(N,N-dimethylaminocarbonyl)-6-methoxyphenyl,
3-(N-ethylaminocarbonyl)-6-methoxyphenyl,
2-methoxy-5-(N-methylaminocarbonyl)phenyl,
2-methoxy-5-(pyrrolidin-1-ylcarbonyl)phenyl,
2-methoxy-5-(N-(2-methylpropyl)aminocarbonyl)phenyl,
2-methoxy-5-(N-(2-(dimethylamino)ethyl)aminocarbonyl)phenyl,
3-(N-(2-hydroxyethyl)aminocarbonyl)-6-methoxyphenyl,
2-methoxy-5-(N-prop-1-ylaminocarbonyl)phenyl,
3-(6-acetyl-2,6-diazaspiro[3.3]heptane-2-ylcarbonyl)-6-methoxyphenyl,
4-(1-hydroxy-1-methylethyl)-2-methoxyphenyl,
4-(1-hydroxy-1-methylethyl)phenyl,
4-(4-methylpiperazin-1-ylcarbonyl)phenyl,
4-(N,N-dimethylaminocarbonyl)phenyl,
3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl,
3-(N-methylaminocarbonyl)phenyl, 4-(hydroxymethyl)phenyl,
3-chloro-4-(N,N-dimethylaminocarbonyl)phenyl,
3-chloro-4-(aminocarbonyl)phenyl, and
3-(azetidine-1-carbonyl)-6-methoxyphenyl.
In certain embodiments Q is:
##STR00004## wherein:
ring A is optionally substituted with one or more groups R.sup.g,
or ring A is optionally fused with a carbocyclyl or a heterocyclyl
to form a polycyclyl that is optionally substituted with one or
more groups R.sup.g;
R.sup.e is hydrogen, --F, --Cl, --Br, --I, --CN, C.sub.1-6alkyl,
C.sub.2-6alkenyl, or C.sub.2-6alkynyl, wherein each C.sub.1-6alkyl,
C.sub.2-6alkenyl, or C.sub.2-6alkynyl is optionally substituted
with one or more groups independently selected from oxo, --F, --Br,
--I, --NO.sub.2, --N(R.sup.x).sub.2, --CN,
--C(O)--N(R.sup.x).sub.2, --S(O)--N(R.sup.x).sub.2,
--S(O).sub.2--N(R.sup.x).sub.2, --O--C(O)--R.sup.x,
--C(O)--O--R.sup.x, --S(O)--R.sup.x, --S(O).sub.2--R.sup.x,
--N(R.sup.x)--C(O)--R.sup.x, --N(R.sup.x)--S(O)--R.sup.x, and
--N(R.sup.x)--S(O).sub.2--R.sup.x;
R.sup.f is hydrogen, --F, --Cl, --Br, --I, --CN, --O--R.sup.y,
C.sub.1-6alkyl, C.sub.2-6alkenyl, or C.sub.2-6alkynyl, wherein each
C.sub.1-6alkyl, C.sub.2-6alkenyl, or C.sub.2-6alkynyl is optionally
substituted with one or more groups independently selected from
oxo, --F, --Cl, --Br, --I, --NO.sub.2, --N(R.sup.y).sub.2, --CN,
--C(O)--N(R.sup.y).sub.2, --S(O)--N(R.sup.y).sub.2,
--S(O).sub.2--N(R.sup.y).sub.2, --O--C(O)--R.sup.y,
--C(O)--R.sup.y, --C(O)--O--R.sup.y, --S(O)--R.sup.y,
--S(O).sub.2--R.sup.y, --N(R.sup.y)--C(O)--R.sup.y,
--N(R.sup.y)--S(O)--R.sup.y and
--N(R.sup.y)--S(O).sub.2--R.sup.y;
each R.sup.g is independently selected from oxo, C.sub.1-6alkyl,
C.sub.2 alkenyl, C.sub.2-6alkynyl, C.sub.1-6haloalkyl, carbocyclyl,
heterocyclyl, --F, --Cl, --Br, --I, --NO.sub.2, --N(R.sup.z).sub.2,
--CN, --C(O)--N(R.sup.z).sub.2, --S(O)--N(R.sup.z).sub.2,
--S(O).sub.2--N(R.sup.z).sub.2, --O--R.sup.z, --O--C(O)--R.sup.z,
--C(O)--R.sup.z, --C(O)--O--R.sup.z, --S(O)--R.sup.z,
--S(O).sub.2--R.sup.z, --O--C(O)--N(R.sup.z).sub.2,
--N(R.sup.z)--C(O)--OR.sup.z, --N(R.sup.z)--C(O)--N(R.sup.z).sub.2,
C(O)--R.sup.z, --N(R.sup.z)--S(O)--R.sup.z,
--N(R.sup.z)--S(O).sub.2--R.sup.z,
--N(R.sup.z)--S(O)--N(R.sup.z).sub.2, and
--N(R.sup.z)--S(O).sub.2--N(R.sup.z).sub.2, wherein any
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6haloalkyl, carbocyclyl, or heterocyclyl is optionally
substituted with one or more groups independently selected from
oxo, halo, --NO.sub.2, --N(R.sup.z).sub.2, --CN,
--C(O)--N(R.sup.z).sub.2, --S(O)--N(R.sup.z).sub.2,
--S(O).sub.2--N(R.sup.z).sub.2, --O--R.sup.z, --S--R.sup.z,
--O--C(O)--R.sup.z, --C(O)--O--R.sup.z, --S(O)--R.sup.z,
--S(O).sub.2--R.sup.z, --N(R.sup.z)--C(O)--R.sup.z,
--N(R.sup.z)--S(O)--R.sup.z, --N(R.sup.z)--S(O).sub.2--R.sup.z and
C.sub.1-6alkyl and heteroaryl wherein C.sub.1-3alkyl is optionally
substituted with one or more groups independently selected from
oxo, hydroxyl, --N(R.sup.ua).sub.2 and halo and heteroaryl is
optionally substituted with one or more --N(R.sup.ua).sub.2;
each R.sup.x is independently selected from hydrogen,
C.sub.1-6alkyl, C.sub.2-6alkenyl, and C.sub.2-6alkynyl, wherein
each C.sub.1-6alkyl, C.sub.2-6alkenyl, or C.sub.2-6alkynyl is
optionally substituted with one or more groups independently
selected from oxo, halo, amino, hydroxyl, and C.sub.1-C.sub.6
alkyl;
each R.sup.y is independently selected from hydrogen,
C.sub.1-6alkyl, C.sub.2-6alkenyl, and C.sub.2-6alkynyl, wherein
each C.sub.1-6alkyl, C.sub.2-6alkenyl, or C.sub.2-6alkynyl is
optionally substituted with one or more groups independently
selected from oxo, halo, amino, hydroxyl, and C.sub.1-C.sub.6
alkyl; and
each R.sup.z is independently selected from hydrogen,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, carbocyclyl,
and heterocyclyl, wherein each C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, carbocyclyl, or heterocyclyl is optionally
substituted with one or more groups independently selected from
oxo, halo, amino, hydroxyl, heterocyclyl, carbocyclyl, and
C.sub.1-C.sub.6 alkyl that is optionally substituted with one or
more groups independently selected from oxo and halo; or two
R.sup.z are taken together with the nitrogen to which they are
attached to form a heterocyclyl that is optionally substituted with
one or more groups independently selected from oxo, halo and
C.sub.1-3alkyl that is optionally substituted with one or more
groups independently selected from oxo and halo.
In certain embodiments R.sup.e is hydrogen.
In certain embodiments R.sup.f is hydrogen.
In certain embodiments the ring A is optionally substituted with
one or more groups R.sup.g.
In certain embodiments R.sup.c is independently selected from oxo,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6haloalkyl, carbocyclyl, heterocyclyl, --F, --Cl,
--N(R.sup.u).sup.2, --CN, --C(O)--N(R.sup.u).sub.2, --O--R.sup.u,
and --N(R.sup.u)--S(O).sub.2--R.sup.u, --wherein any
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6haloalkyl, carbocyclyl, or heterocyclyl is optionally
substituted with one or more groups independently selected from
oxo, halo, --NO.sub.2, --N(R.sup.u).sub.2, --CN,
--C(O)--N(R.sup.u).sub.2, --S(O)--N(R.sup.u).sub.2,
--S(O).sub.2--N(R.sup.u).sub.2, --O--R.sup.u, --S--R.sup.u,
--O--C(O)--R.sup.u, --C(O)--R.sup.u, --C(O)--O--R.sup.u,
--S(O)--R.sup.u, --S(O).sub.2--R.sup.u,
--N(R.sup.u)--C(O)--R.sup.u, --N(R.sup.u)--S(O)--R.sup.u,
--N(R.sup.u)--S(O).sub.2--R.sup.u and C.sub.1-6alkyl that is
optionally substituted with one or more groups independently
selected from oxo and halo.
In certain embodiments R.sup.c is independently selected from oxo,
heterocyclyl, --F, --Cl, --CN, --C(O)--N(R.sup.u).sub.2,
--O--R.sup.u, and --N(R.sup.u)--S(O).sub.2--R.sup.u, wherein any
C.sub.1-6alkyl or heterocyclyl is optionally substituted with one
or more groups independently selected from oxo, halo, --NO.sub.2,
--N(R.sup.u).sub.2, --CN, --C(O)--N(R.sup.u).sub.2,
--S(O)--N(R.sup.u).sub.2, --S(O).sub.2--N(R.sup.u).sub.2,
--O--C(O)--R.sup.u, --C(O)--R.sup.u, --C(O)--O--R.sup.u,
--S(O)--R.sup.u, --S(O).sub.2--R.sup.u,
--N(R.sup.u)--C(O)--R.sup.u, --N(R.sup.u)--S(O)--R.sup.u,
--N(R.sup.u)--S(O).sub.2--R.sup.u and C.sub.1-6alkyl that is
optionally substituted with one or more groups independently
selected from oxo and halo.
In certain embodiments R.sup.c is independently selected from oxo,
heterocyclyl, --F, --Cl, --CN, --C(O)--N(R.sup.u).sub.2,
--O--R.sup.u, and --N(R.sup.u)--S(O).sub.2--R.sup.u, wherein any
C.sub.1-6alkyl or heterocyclyl is optionally substituted with one
or more groups independently selected from --O--R.sup.u and
C.sub.1-6alkyl that is optionally substituted with one or more
groups independently selected from oxo and halo.
In certain embodiments Q is substituted with one
--C(O)--N(R.sup.u).sub.2 group and optionally substituted with one
or more R.sup.c groups independently selected from C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6haloalkyl,
carbocyclyl, heterocyclyl, --F, --Cl, --N(R.sup.u).sub.2, --CN,
--C(O)--N(R.sup.u).sub.2--O--R.sup.u, and
--N(R.sup.u)--S(O).sub.2--R.sup.u, --wherein any C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6haloalkyl,
carbocyclyl, or heterocyclyl is optionally substituted with one or
more groups independently selected from oxo, halo, --NO.sub.2,
--N(R.sup.u).sub.2, --CN, --C(O)--N(R.sup.u).sub.2,
--S(O)--N(R.sup.u).sub.2, --S(O).sub.2--N(R.sup.u).sub.2,
--S--R.sup.u, --O--C(O)--R.sup.u, --C(O)--R.sup.u,
--C(O)--O--R.sup.u, --S(O)--R.sup.u, --S(O).sub.2--R.sup.u,
--N(R.sup.u)--C(O)--R.sup.u, --N(R.sup.u)--S(O)--R.sup.u,
--N(R.sup.u)--S(O).sub.2--R.sup.u and C.sub.1-6alkyl that is
optionally substituted with one or more groups independently
selected from oxo and halo.
In certain embodiments Q is phenyl that is substituted with a group
--C(O)--N(R.sup.u).sub.2, and that is optionally substituted with
one or more groups R.sup.c, wherein each R.sup.c is independently
selected from C.sub.1-6alkyl, heterocyclyl, --F, --Cl, --CN,
--C(O)--N(R.sup.u).sub.2, and --O--R.sup.u, wherein any
C.sub.1-6alkyl or heterocyclyl is optionally substituted with one
or more groups independently selected from --O--R.sup.u and
C.sub.1-6alkyl that is optionally substituted with one or more
groups independently selected from oxo and halo.
In certain embodiments Q is selected from:
##STR00005## ##STR00006## ##STR00007## ##STR00008## ##STR00009##
##STR00010## ##STR00011## ##STR00012## ##STR00013##
In certain embodiments the compound is selected from:
3-(6-allyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N,N-dimethylbenzamide;
3-(6-butyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N,N-dimethylbenzamide;
N,N-dimethyl-3-[6-(3-methylbut-2-enyl)-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-y-
l]benzamide;
3-[6-(2-cyclopropylethyl)-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N,N-dimeth-
ylbenzamide;
3-[6-(cyclopentylmethyl)-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N,N-dimethy-
lbenzamide;
3-[6-[(4-methoxyphenyl)methyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N,N-d-
imethylbenzamide;
N,N-dimethyl-3-[7-oxo-6-[(E)-pent-2-enyl]-1H-pyrrolo[2,3-c]pyridin-4-yl]b-
enzamide;
3-(6-but-3-enyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N,N-dimethy-
lbenzamide;
3-[6-(cyclohexylmethyl)-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N,N-dimethyl-
benzamide;
3-(6-isopentyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N,N-dimethy-
lbenzamide; 3
[6-(cyclobutylmethyl)-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N,N-dimethylbe-
nzamide;
3-[6-(2-cyclohexylethyl)-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N,N-
-dimethylbenzamide;
N,N-dimethyl-3-(7-oxo-6-pentyl-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide;
3-[6-(2-methoxyethyl)-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N,N-dimethylbe-
nzamide;
3-[6-(3-methoxypropyl)-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N,N-d-
imethylbenzamide;
3-(6-isobutyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N,N-dimethylbenzamide;
3-(6-(cyclopropylmethyl)-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N,N-dimethy-
lbenzamide;
6-but-3-enyl-4-[3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]-1H-pyrrolo[2,3-c-
]pyridin-7-one;
3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-5-fluoro-N,N-d-
imethylbenzamide;
4-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-2-fluorobenzam-
ide;
6-but-2-enyl-4-[4-(4-methylpiperazine-1-carbonyl)phenyl]-1H-pyrrolo[2-
,3-c]pyridin-7-one;
3-(6-but-2-enyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-5-fluorobenzamide;
6-but-2-enyl-4-(4-tert-butylphenyl)-1H-pyrrolo[2,3-c]pyridin-7-one;
4-(6-but-2-enyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-methylbenzamide;
3-(6-but-2-enyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-methylbenzamide;
3-(6-but-2-enyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-cyclopropylbenzami-
de;
6-but-2-enyl-4-[3-(pyrrolidine-1-carbonyl)phenyl]-1H-pyrrolo[2,3-c]pyr-
idin-7-one;
4-(6-but-2-enyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-cyclopropylbenzami-
de;
6-but-2-enyl-4-[4-(hydroxymethyl)phenyl]-1H-pyrrolo[2,3-c]pyridin-7-on-
e; 3-(6-but-2-enyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide;
6-but-2-enyl-4-(4-isopropylphenyl)-1H-pyrrolo[2,3-c]pyridin-7-one;
3-(6-but-2-enyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N,N-dimethylbenzamid-
e;
6-but-2-enyl-4-[4-(pyrrolidine-1-carbonyl)phenyl]-1H-pyrrolo[2,3-c]pyri-
din-7-one;
N-[4-(6-but-2-enyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]m-
ethanesulfonamide;
3-(6-but-2-enyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-isopropylbenzamide-
;
4-(6-but-2-enyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N,N-dimethylbenzami-
de;
6-but-2-enyl-4-[4-(morpholine-4-carbonyl)phenyl]-1H-pyrrolo[2,3-c]pyri-
din-7-one;
3-(6-but-2-enyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-methoxy--
benzonitrile;
3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-2-fluorobenzam-
ide;
3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-4-fluorobe-
nzamide;
3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-4-fluo-
ro-N,N-dimethylbenzamide;
3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-2-fluoro-N,N-d-
imethylbenzamide;
4-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-2-chloro-N,N-d-
imethylbenzamide;
4-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-2-chlorobenzam-
ide; 6-(2-furylmethyl)-4-phenyl-1H-pyrrolo[2,3-c]pyridin-7-one;
3-(6-butyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-methoxy-benzonitrile;
3-[6-(2-cyclopropylethyl)-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-4-methoxy--
benzonitrile;
3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N-cyclopropyl--
4-methoxybenzamide;
3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-4-methoxy-N,N--
dimethylbenzamide;
3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-4-methoxy-N-te-
trahydrofuran-3-ylbenzamide;
3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N-ethyl-4-meth-
oxybenzamide;
3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-4-methoxy-N-me-
thylbenzamide;
6-[(E)-but-2-enyl]-4-[2-methoxy-5-(pyrrolidine-1-carbonyl)phenyl]-1H-pyrr-
olo[2,3-c]pyridin-7-one;
3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N-(2,2-difluor-
oethyl)-4-methoxybenzamide;
3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N-isobutyl-4-m-
ethoxybenzamide;
4-[5-(azetidine-1-carbonyl)-2-methoxy-phenyl]-6-[(E)-but-2-enyl]-1H-pyrro-
lo[2,3-c]pyridin-7-one;
3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N-[2-(dimethyl-
amino)ethyl]-4-methoxybenzamide;
3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N-(2-hydroxyet-
hyl)-4-methoxybenzamide;
3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-4-methoxy-N-pr-
opylbenzamide;
3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N-cyclobutyl-4-
-methoxybenzamide;
3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N-(cyclopropyl-
methyl)-4-methoxybenzamide;
4-[5-(6-acetyl-2,6-diazaspiro[3.3]heptane-2-carbonyl)-2-methoxy-phenyl]-6-
-[(E)-but-2-enyl]-1H-pyrrolo[2,3-c]pyridin-7-one;
4-[5-(6-acetyl-2,6-diazaspiro[3.3]heptane-2-carbonyl)-2-methoxy-phenyl]-6-
-butyl-1H-pyrrolo[2,3-c]pyridin-7-one;
6-[(E)-but-2-enyl]-4-[4-(1-hydroxy-1-methyl-ethyl)-2-methoxy-phenyl]-1H-p-
yrrolo[2,3-c]pyridin-7-one;
6-butyl-4-[4-(1-hydroxy-1-methyl-ethyl)-2-methoxy-phenyl]-1H-pyrrolo[2,3--
c]pyridin-7-one;
6-[(E)-but-2-enyl]-4-[4-(1-hydroxy-1-methyl-ethyl)phenyl]-1H-pyrrolo[2,3--
c]pyridin-7-one;
6-butyl-4-(4-(2-hydroxypropan-2-yl)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-
-one;
6-(2-cyclopropylethyl)-4-[4-(1-hydroxy-1-methyl-ethyl)phenyl]-1H-pyr-
rolo[2,3-c]pyridin-7-one;
3-(6-(2-cyclopropylethyl)-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyr-
idin-4-yl)-N,N-dimethylbenzamide;
3-(6-butyl-2-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N,N-dimethylbenz-
amide;
3-(6-butyl-2-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-methoxy--
N,N-dimethylbenzamide;
3-[6-(2-cyclopropylethyl)-2-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-4-
-methoxy-N,N-dimethylbenzamide; and
7-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-4-methyl-1,3,4-
,5-tetrahydro-1,5-benzodiazepin-2-one; and salts thereof. In
certain embodiments the compound is selected from:
6-but-3-enyl-4-[3,4-difluoro-5-(morpholine-4-carbonyl)phenyl]-1H-pyrrolo[-
2,3-c]pyridin-7-one;
6-but-3-enyl-4-[3-fluoro-5-(3-methylmorpholine-4-carbonyl)phenyl]-1H-pyrr-
olo[2,3-c]pyridin-7-one;
3-(6-but-3-enyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-5-(morpholine-4-carb-
onyl)benzonitrile
6-[(E)-but-2-enyl]-4-[3-chloro-4-(morpholine-4-carbonyl)phenyl]-1H-pyrrol-
o[2,3-c]pyridin-7-one;
6-[(E)-but-2-enyl]-4-[3-chloro-4-(pyrrolidine-1-carbonyl)phenyl]-1H-pyrro-
lo[2,3-c]pyridin-7-one;
6-but-3-enyl-4-[3-fluoro-5-(morpholine-4-carbonyl)phenyl]-1H-pyrrolo[2,3--
c]pyridin-7-one;
6-but-3-enyl-4-[4-fluoro-3-(morpholine-4-carbonyl)phenyl]-1H-pyrrolo[2,3--
c]pyridin-7-one;
6-but-3-enyl-4-[3-(difluoromethoxy)-5-(morpholine-4-carbonyl)phenyl]-1H-p-
yrrolo[2,3-c]pyridin-7-one;
6-but-3-enyl-4-[6-(morpholine-4-carbonyl)-1H-benzimidazol-4-yl]-1H-pyrrol-
o[2,3-c]pyridin-7-one;
7-(6-but-3-enyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N,N-dimethyl-3H-benz-
imidazole-5-carboxamide;
6-but-3-enyl-4-[7-(morpholine-4-carbonyl)-3H-benzimidazol-5-yl]-1H-pyrrol-
o[2,3-c]pyridin-7-one;
6-but-3-enyl-4-[3-methyl-7-(morpholine-4-carbonyl)benzimidazol-5-yl]-1H-p-
yrrolo[2,3-e]pyridin-7-one;
6-but-3-enyl-4-[3-ethyl-7-(morpholine-4-carbonyl)benzimidazol-5-yl]-1H-py-
rrolo[2,3-c]pyridin-7-one;
6-but-3-enyl-4-[1-methyl-7-(morpholine-4-carbonyl)benzimidazol-5-yl]-1H-p-
yrrolo[2,3-c]pyridin-7-one;
6-but-3-enyl-4-[1-methyl-6-(morpholine-4-carbonyl)benzimidazol-4-yl]-1H-p-
yrrolo[2,3-c]pyridin-7-one;
6-but-3-enyl-4-[4-chloro-3-(morpholine-4-carbonyl)phenyl]-2-methyl-1H-pyr-
rolo[2,3-c]pyridin-7-one;
6-[(E)-but-2-enyl]-2-methyl-4-[4-(morpholine-4-carbonyl)phenyl]-1H-pyrrol-
o[2,3-c]pyridin-7-one;
6-[(E)-but-2-enyl]-2-methyl-4-[4-(pyrrolidine-1-carbonyl)phenyl]-1H-pyrro-
lo[2,3-c]pyridin-7-one
6-[(E)-but-2-enyl]-4-[3-chloro-4-(pyrrolidine-1-carbonyl)phenyl]-2-methyl-
-1H-pyrrolo[2,3-c]pyridin-7-one;
6-[(E)-but-2-enyl]-4-[2,3-difluoro-4-(morpholine-4-carbonyl)phenyl]-2-met-
hyl-1H-pyrrolo[2,3-c]pyridin-7-one;
6-[(E)-but-2-enyl]-4-[3-methoxy-4-(morpholine-4-carbonyl)phenyl]-2-methyl-
-1H-pyrrolo[2,3-c]pyridin-7-one;
6-[(E)-but-2-enyl]-4-[3-chloro-4-(morpholine-4-carbonyl)phenyl]-2-methyl--
1H-pyrrolo[2,3-c]pyridin-7-one;
6-but-3-enyl-4-[3-fluoro-5-(morpholine-4-carbonyl)phenyl]-2-methyl-1H-pyr-
rolo[2,3-e]pyridin-7-one;
6-but-3-enyl-4-[4-fluoro-3-(morpholine-4-carbonyl)phenyl]-2-methyl-1H-pyr-
rolo[2,3-c]pyridin-7-one;
6-[(E)-but-2-enyl]-4-[5-chloro-6-(morpholine-4-carbonyl)-3-pyridyl]-2-met-
hyl-1H-pyrrolo[2,3-c]pyridin-7-one;
6-[(E)-but-2-enyl]-4-[3-chloro-4-(4-methylpiperazine-1-carbonyl)phenyl]-2-
-methyl-1H-pyrrolo[2,3-c]pyridin-7-one;
6-[(E)-but-2-enyl]-2-methyl-4-[3-methyl-4-(morpholine-4-carbonyl)phenyl]--
1H-pyrrolo[2,3-c]pyridin-7-one;
6-allyl-4-[3-chloro-4-(morpholine-4-carbonyl)phenyl]-2-methyl-1H-pyrrolo[-
2,3-c]pyridin-7-one;
6-allyl-4-[2,5-dimethoxy-4-(morpholine-4-carbonyl)phenyl]-2-methyl-1H-pyr-
rolo[2,3-c]pyridin-7-one;
6-[(E)-but-2-enyl]-4-[3-methoxy-5-(morpholine-4-carbonyl)-2-pyridyl]-2-me-
thyl-1H-pyrrolo[2,3-c]pyridin-7-one;
6-[(E)-but-2-enyl]-4-[4-chloro-5-(morpholine-4-carbonyl)-2-pyridyl]-2-met-
hyl-1H-pyrrolo[2,3-c]pyridin-7-one;
6-[(E)-but-2-enyl]-2-methyl-4-[2-(morpholine-4-carbonyl)pyrimidin-5-yl]-1-
H-pyrrolo[2,3-c]pyridin-7-one;
5-[6-[(E)-but-2-enyl]-2-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-2-(mo-
rpholine-4-carbonyl)benzonitrile;
6-[(E)-but-2-enyl]-4-[4-(1-hydroxy-1-methyl-ethyl)-2-methoxy-phenyl]-2-me-
thyl-1H-pyrrolo[2,3-c]pyridin-7-one
6-[(E)-but-2-enyl]-4-[2,5-dimethoxy-4-(morpholine-4-carbonyl)phenyl]-2-me-
thyl-1H-pyrrolo[2,3-c]pyridin-7-one;
3-[6-[(E)-but-2-enyl]-2-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-4-met-
hoxy-N-(pyrazin-2-ylmethyl)benzamide
6-but-2-enyl-4-[3-methoxy-5-(4-methylpiperazine-1-carbonyl)-2-pyridyl]-2--
methyl-1H-pyrrolo[2,3-c]pyridin-7-one;
6-[(E)-but-2-enyl]-4-[6-chloro-5-(morpholine-4-carbonyl)-2-pyridyl]-2-met-
hyl-1H-pyrrolo[2,3-c]pyridin-7-one;
1-[4-[6-[(E)-but-2-enyl]-2-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-2--
chloro-benzoyl]piperidine-4-carboxylic acid;
1-[4-[6-[(E)-but-2-enyl]-2-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-2--
chloro-benzoyl]piperidine-4-carboxamide;
6-[(E)-but-2-enyl]-4-[3-isopropoxy-4-(morpholine-4-carbonyl)phenyl]-2-met-
hyl-1H-pyrrolo[2,3-c]pyridin-7-one;
6-[(E)-but-2-enyl]-4-[3-(cyclopropylmethoxy)-4-(morpholine-4-carbonyl)phe-
nyl]-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-one;
6-[(E)-but-2-enyl]-4-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-2-methyl--
1H-pyrrolo[2,3-c]pyridin-7-one;
4-[4-[3-(3-aminopyrazol-1-yl)azetidine-1-carbonyl]-3-chloro-phenyl]-6-[(E-
)-but-2-enyl]-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-one;
4-[4-[3-(3-aminopyrazol-1-yl)azetidine-1-carbonyl]phenyl]-6-[(E)-but-2-en-
yl]-2-methyl-1H-pyrrolo[2,3-c]pyrine;
6-[(E)-but-2-enyl]-4-[4-(1-hydroxy-1-methyl-ethyl)-2,5-dimethoxy-phenyl]--
2-methyl-1H-pyrrolo[2,3-c]pyridin-7-one;
3-[6-[(E)-but-2-enyl]-2-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-4-met-
hoxy-N-(pyrimidin-5-ylmethyl)benzamide;
6-butyl-4-[2,5-dimethoxy-4-(morpholine-4-carbonyl)phenyl]-2-methyl-1H-pyr-
rolo[2,3-c]pyridin-7-one;
6-butyl-4-[3-methoxy-5-(4-methylpiperazine-1-carbonyl)-2-pyridyl]-2-methy-
l-1H-pyrrolo[2,3-c]pyridin-7-one; and
6-butyl-4-[3-methoxy-5-(morpholine-4-carbonyl)-2-pyridyl]-2-methyl-1H-pyr-
rolo[2,3-c]pyridin-7-one and salts thereof.
In certain embodiments the compound is selected from:
TABLE-US-00001 Structure Name ##STR00014## 3-(6-allyl-7-oxo-1H-
pyrrolo[2,3-c]pyridin-4-yl)- N,N-dimethyl-benzamide ##STR00015##
3-(6-butyl-7-oxo-1H- pyrrolo[2,3-c]pyridin-4-yl)-
N,N-dimethyl-benzamide ##STR00016## N,N-dimethyl-3-[6-(3-
methylbut-2-enyl)-7-oxo-1H- pyrrolo[2,3-c]pyridin-4- yl]benzamide
##STR00017## 3-[6-(2-cyclopropylethyl)-7-
oxo-1H-pyrrolo[2,3-c]pyridin- 4-yl]-N,N-dimethyl- benzamide
##STR00018## 3-[6-(cyclopentylmethyl)-7-
oxo-1H-pyrrolo[2,3-c]pyridin- 4-yl]-N,N-dimethyl- benzamide
##STR00019## 3-[6-[(4- methoxyphenyl)methyl]-7-
oxo-1H-pyrrolo[2,3-c]pyridin- 4-yl]-N,N-dimethyl- benzamide
##STR00020## N,N-dimethyl-3-[7-oxo-6- [(E)-pent-2-enyl]-1H-
pyrrolo[2,3-c]pyridin-4- yl]benzamide ##STR00021##
3-(6-but-2-enyl-7-oxo-1H- pyrrolo[2,3-c]pyridin-4-yl)-
N,N-dimethyl-benzamide ##STR00022## 3-[6-(cyclohexylmethyl)-7-
oxo-1H-pyrrolo[2,3-c]pyridin- 4-yl]-N,N-dimethyl- benzamide
##STR00023## 3-(6-isopentyl-7-oxo-1H- pyrrolo[2,3-c]pyridin-4-yl)-
N,N-dimethyl-benzamide ##STR00024## 3-[6-(cyclobutylmethyl)-7-
oxo-1H-pyrrolo[2,3-c]pyridin- 4-yl]-N,N-dimethyl- benzamide
##STR00025## 3-[6-(2-cyclohexylethyl)-7-
oxo-1H-pyrrolo[2,3-c]pyridin- 4-yl]-N,N-dimethyl- benzamide
##STR00026## N,N-dimethyl-3-(7-oxo-6- pentyl-1H-pyrrolo[2,3-
c]pyridin-4-yl)benzamide ##STR00027## 3-[6-(2-methoxyethyl)-7-oxo-
1H-pyrrolo[2,3-c]pyridin-4- yl]-N,N-dimethyl-benzamide ##STR00028##
3-[6-(3-methoxypropyl)-7- oxo-1H-pyrrolo[2,3-c]pyridin-
4-yl]-N,N-dimethyl- benzamide ##STR00029## 3-(6-isobutyl-7-oxo-1H-
pyrrolo[2,3-c]pyridin-4-yl)- N,N-dimethyl-benzamide ##STR00030##
3-[6-(cyclopropylmethyl)-7- oxo-1H-pyrrolo[2,3-c]pyridin-
4-yl]-N,N-dimethyl- benzamide ##STR00031##
6-but-3-enyl-4-[3-(5-methyl- 1,3,4-oxadiazol-2-yl)phenyl]-
1H-pyrrolo[2,3-c]pyridin-7- one ##STR00032##
3-[6-[(E)-but-2-enyl]-7-oxo- 1H-pyrrolo[2,3-c]pyridin-4-
yl]-5-fluoro-N,N-dimethyl- benzamide ##STR00033##
4-[6-[(E)-but-2-enyl]-7-oxo- 1H-pyrrolo[2,3-c]pyridin-4-
yl]-2-fluoro-benzamide ##STR00034## 6-[(E)-but-2-enyl]-4-[4-(4-
methylpiperazine-1- carbonyl)phenyl]-1H-
pyrrolo[2,3-c]pyridin-7-one ##STR00035##
3-[6-[(E)-but-2-enyl]-7-oxo- 1H-pyrrolo[2,3-c]pyridin-4-
yl]-5-fluoro-benzamide ##STR00036## 6-[(E)-but-2-enyl]-4-(4-tert-
butylphenyl)-1H-pyrrolo[2,3- c]pyridin-7-one ##STR00037##
4-[6-[(E)-but-2-enyl]-7-oxo- 1H-pyrrolo[2,3-c]pyridin-4-
yl]-N-methyl-benzamide ##STR00038## 3-[6-[(E)-but-2-enyl]-7-oxo-
1H-pyrrolo[2,3-c]pyridin-4- yl]-N-methyl-benzamide ##STR00039##
3-[6-[(E)-but-2-enyl]-7-oxo- 1H-pyrrolo[2,3-c]pyridin-4-
yl]-N-cyclopropyl-benzamide ##STR00040## 6-[(E)-but-2-enyl]-4-[3-
(pyrrolidine-1- carbonyl)phenyl]-1H- pyrrolo[2,3-c]pyridin-7-one
##STR00041## 4-[6-[(E)-but-2-enyl]-7-oxo-
1H-pyrrolo[2,3-c]pyridin-4- yl]-N-cyclopropyl-benzamide
##STR00042## 6-[(E)-but-2-enyl]-4-[4- (hydroxymethyl)phenyl]-1H-
pyrrolo[2,3-c]pyridin-7-one ##STR00043##
3-[6-[(E)-but-2-enyl]-7-oxo- 1H-pyrrolo[2,3-c]pyridin-4-
yl]benzamide ##STR00044## 6-[(E)-but-2-enyl]-4-(4-
isopropylphenyl)-1H- pyrrolo[2,3-c]pyridin-7-one ##STR00045##
3-[6-[(E)-but-2-enyl]-7-oxo- 1H-pyrrolo[2,3-c]pyridin-4-
yl]-N,N-dimethyl-benzamide ##STR00046## 6-[(E)-but-2-enyl]-4-[4-
(pyrrolidine-1- carbonyl)phenyl]-1H- pyrrolo[2,3-c]pyridin-7-one
##STR00047## N-[4-[6-[(E)-but-2-enyl]-7-
oxo-1H-pyrrolo[2,3-c]pyridin- 4- yl]phenyl]methanesulfonamide
##STR00048## 3-[6-[(E)-but-2-enyl]-7-oxo-
1H-pyrrolo[2,3-c]pyridin-4- yl]-N-isopropyl-benzamide ##STR00049##
4-[6-[(E)-but-2-enyl]-7-oxo- 1H-pyrrolo[2,3-c]pyridin-4-
yl]-N,N-dimethyl-benzamide ##STR00050## 6-[(E)-but-2-enyl]-4-[4-
(morpholine-4- carbonyl)phenyl]-1H- pyrrolo[2,3-c]pyridin-7-one
##STR00051## 3-[6-[(E)-but-2-enyl]-7-oxo-
1H-pyrrolo[2,3-c]pyridin-4- yl]-4-methoxy-benzonitrile ##STR00052##
3-[6-[(E)-but-2-enyl]-7-oxo- 1H-pyrrolo[2,3-c]pyridin-4-
yl]-2-fluoro-benzamide ##STR00053## 3-[6-[(E)-but-2-enyl]-7-oxo-
1H-pyrrolo[2,3-c]pyridin-4- yl]-4-fluoro-benzamide ##STR00054##
3-[6-[(E)-but-2-enyl]-7-oxo- 1H-pyrrolo[2,3-c]pyridin-4-
yl]-4-fluoro-N,N-dimethyl- benzamide ##STR00055##
3-[6-[(E)-but-2-enyl]-7-oxo- 1H-pyrrolo[2,3-c]pyridin-4-
yl]-fluoro-N,N-dimethyl- benzamide ##STR00056##
4-[6-[(E)-but-2-enyl]-7-oxo- 1H-pyrrolo[2,3-c]pyridin-4-
yl]-2-chloro-N,N-dimethyl- benzamide ##STR00057##
4-[6-[(E)-but-2-enyl]-7-oxo- 1H-pyrrolo[2,3-c]pyridin-4-
yl]-2-chloro-benzamide ##STR00058## 6-(2-furylmethyl)-4-phenyl-
1H-pyrrolo[2,3-c]pyridin-7- one ##STR00059## 3-(6-butyl-7-oxo-1H-
pyrrolo[2,3-c]pyridin-4-yl)-4- methoxy-benzonitrile ##STR00060##
3-[6-(2-cyclopropylethyl)-7- oxo-1H-pyrrolo[2,3-c]pyridin-
4-yl]-4-methoxy-benzonitrile ##STR00061##
6-but-3-enyl-4-[3,4-difluoro-5- (morpholine-4- carbonyl)phenyl]-1H-
pyrrolo[2,3-c]pyridin-7-one ##STR00062##
6-but-3-enyl-4-[3-fluoro-5-(3- methylmorpholine-4-
carbonyl)phenyl]-1H- pyrrolo[2,3-c]pyridin-7-one ##STR00063##
3-(6-but-3-enyl-7-oxo-1H- pyrrolo[2,3-c]pyridin-4-yl)-5-
(morpholine-4- carbonyl)benzonitrile ##STR00064##
6-[(E)-but-2-enyl]-4-[3- chloro-4-(morpholine-4-
carbonyl)phenyl]-1H- pyrrolo[2,3-c]pyridin-7-one ##STR00065##
6-[(E)-but-2-enyl]-4-[3- chloro-4-(pyrrolidine-1-
carbonyl)phenyl]-1H- pyrrolo[2,3-c]pyridin-7-one ##STR00066##
6-but-3-enyl-4-[3-fluoro-5- (morpholine-4- carbonyl)phenyl]-1H-
pyrrolo[2,3-c]pyridin-7-one ##STR00067##
6-but-3-enyl-4-[4-fluoro-3- (morpholine-4- carbonyl)phenyl]-1H-
pyrrolo[2,3-c]pyridin-7-one ##STR00068## 6-but-3-enyl-4-[3-
(difluoromethoxy)-5- (morpholine-4- carbonyl)phenyl]-1H-
pyrrolo[2,3-c]pyridin-7-one ##STR00069## 6-but-3-enyl-4-[6-
(morpholine-4-carbonyl)-1H- benzimidazol-4-yl]-1H-
pyrrolo[2,3-c]pyridin-7-one ##STR00070## 7-(6-but-3-enyl-7-oxo-1H-
pyrrolo[2,3-c]pyridin-4-yl)- N,N-dimethyl-3H-
benzimidazole-5-carboxamide ##STR00071## 6-but-3-enyl-4-[7-
(morpholine-4-carbonyl)-3H- benzimidazol-5-yl]-1H-
pyrrolo[2,3-c]pyridin-7-one ##STR00072##
6-but-3-enyl-4-[3-methyl-7- (morpholine-4-
carbonyl)benzimidazol-5-yl]- 1H-pyrrolo[2,3-c]pyridin-7- one
##STR00073## 6-but-3-enyl-4-[3-ethyl-7- (morpholine-4-
carbonyl)benzimidazol-5-yl]- 1H-pyrrolo[2,3-c]pyridin-7- one
##STR00074## 6-but-3-enyl-4-[1-methyl-7- (morpholine-4-
carbonyl)benzimidazol-5-yl]- 1H-pyrrolo[2,3-c]pyridin-7- one
##STR00075## 6-but-3-enyl-4-[1-methyl-6- (morpholine-4-
carbonyl)benzimidazol-4-yl]- 1H-pyrrolo[2,3-c]pyridin-7- one
##STR00076## 3-[6-[(E)-but-2-enyl]-7-oxo-
1H-pyrrolo[2,3-c]pyridin-4- yl]-N-cyclopropyl-4-methoxy- benzamide
##STR00077## 3-[6-[(E)-but-2-enyl]-7-oxo-
1H-pyrrolo[2,3-c]pyridin-4- yl]-4-methoxy-N,N-dimethyl- benzamide
##STR00078## 3-[6-[(E)-but-2-enyl]-7-oxo-
1H-pyrrolo[2,3-c]pyridin-4- yl]-4-methoxy-N- tetrahydrofuran-3-yl-
benzamide ##STR00079## 3-[6-[(E)-but-2-enyl]-7-oxo-
1H-pyrrolo[2,3-c]pyridin-4- yl]-N-ethyl-4-methoxy- benzamide
##STR00080## 3-[6-[(E)-but-2-enyl]-7-oxo-
1H-pyrrolo[2,3-c]pyridin-4- yl]-4-methoxy-N-methyl- benzamide
##STR00081## 6-[(E)-but-2-enyl]-4-[2- methoxy-5-(pyrrolidine-1-
carbonyl)phenyl]-1H- pyrrolo[2,3-c]pyridin-7-one ##STR00082##
3-[6-[(E)-but-2-enyl]-7-oxo- 1H-pyrrolo[2,3-c]pyridin-4-
yl]-N-(2,2-difluoroethyl)-4- methoxy-benzamide ##STR00083##
3-[6-[(E)-but-2-enyl]-7-oxo- 1H-pyrrolo[2,3-c]pyridin-4-
yl]-N-isobutyl-4-methoxy- benzamide ##STR00084##
4-[5-(azetidine-1-carbonyl)-2- methoxy-phenyl]-6-[(E)-but-2-
enyl]-1H-pyrrolo[2,3- c]pyridin-7-one ##STR00085##
3-[6-[(E)-but-2-enyl]-7-oxo- 1H-pyrrolo[2,3-c]pyridin-4- yl]-N-[2-
(dimethylamino)ethyl]-4- methoxy-benzamide ##STR00086##
3-[6-[(E)-but-2-enyl]-7-oxo- 1H-pyrrolo[2,3-c]pyridin-4-
yl]-N-(2-hydroxyethyl)-4- methoxy-benzamide ##STR00087##
3-[6-[(E)-but-2-enyl]-7-oxo- 1H-pyrrolo[2,3-c]pyridin-4-
yl]-4-methoxy-N-propyl- benzamide ##STR00088##
3-[6-[(E)-but-2-enyl]-7-oxo- 1H-pyrrolo[2,3-c]pyridin-4-
yl]-N-cyclobutyl-4-methoxy- benzamide ##STR00089##
3-[6-[(E)-but-2-enyl]-7-oxo- 1H-pyrrolo[2,3-c]pyridin-4-
yl]-N-(cyclopropylmethyl)-4- methoxy-benzamide ##STR00090##
4-[5-(2-acetyl-2,6- diazaspiro[3.3]heptane-6-
carbonyl)-2-methoxy-phenyl]- 6-[(E)-but-2-enyl]-1H-
pyrrolo[2,3-c]pyridin-7-one ##STR00091## 4-[5-(2-acetyl-2,6-
diazaspiro[3.3]heptane-6- carbonyl)-2-methoxy-phenyl]-
6-butyl-1H-pyrrolo[2,3- c]pyridin-7-one ##STR00092##
6-[(E)-but-2-enyl]-4-[4-(1- hydroxy-1-methyl-ethyl)-2-
methoxy-phenyl]-1H- pyrrolo[2,3-c]pyridin-7-one ##STR00093##
6-butyl-4-[4-(1-hydroxy-1- methyl-ethyl)-2-methoxy-
phenyl]-1H-pyrrolo[2,3- c]pyridin-7-one ##STR00094##
6-[(E)-but-2-enyl]-4-[4-(1- hydroxy-1-methyl-
ethyl)phenyl]-1H-pyrrolo[2,3- c]pyridin-7-one ##STR00095##
6-butyl-4-[4-(1-hydroxy-1- methyl-ethyl)phenyl]-1H-
pyrrolo[2,3-c]pyridin-7-one
##STR00096## 6-(2-cyclopropylethyl)-4-[4- (1-hydroxy-1-methyl-
ethyl)phenyl]-1H-pyrrolo[2,3- c]pyridine-7-one ##STR00097##
7-[6-[(E)-but-2-enyl]-7-oxo- 1H-pyrrolo[2,3-c]pyridin-4-
yl]-4-methyl-1,3,4,5- tetrahydro-1,5-benzodiazepin- 2-one
##STR00098## 3-[6-(2-cyclopropylethyl)-2-
methyl-7-oxo-1H-pyrrolo[2,3- c]pyridin-4-yl]-N,N-dimethyl-
benzamide ##STR00099## 3-(6-butyl-2-methyl-7-oxo-
1H-pyrrolo[2,3-c]pyridin-4- yl)-N,N-dimethyl-benzamide ##STR00100##
3-(6-butyl-2-methyl-7-oxo- 1H-pyrrolo[2,3-c]pyridin-4-
yl)-4-methoxy-N,N-dimethyl- benzamide ##STR00101##
3-[6-(2-cyclopropylethyl)-2- methyl-7-oxo-1H-pyrrolo[2,3-
c]pyridin-4-yl]-4-methoxy- N,N-dimethyl-benzamide ##STR00102##
6-but-3-enyl-4-[4-chloro-3- (morpholine-4-
carbonyl)phenyl]-2-methyl- 1H-pyrrolo[2,3-c]pyridin-7- one
##STR00103## 6-[(E)-but-2-enyl]-2-methyl-4- [4-(morpholine-4-
carbonyl)phenyl]-1H- pyrrolo[2,3-c]pyridin-7-one ##STR00104##
6-[(E)-but-2-enyl]-2-methyl-4- [4-(pyrrolidine-1-
carbonyl)phenyl]-1H- pyrrolo[2,3-c]pyridin-7-one ##STR00105##
6-[(E)-but-2-enyl]-4-[3- chloro-4-(pyrrolidine-1-
carbonyl)phenyl]-2-methyl- 1H-pyrrolo[2,3-c]pyridin-7- one
##STR00106## 6-[(E)-but-2-enyl]-4-[2,3- difluoro-4-(morpholine-4-
carbonyl)phenyl]-2-methyl- 1H-pyrrolo[2,3-c]pyridin-7- one
##STR00107## 6-[(E)-but-2-enyl]-4-[3- methoxy-4-(morpholine-4-
carbonyl)phenyl]-2-methyl- 1H-pyrrolo[2,3-c]pyridin-7- one
##STR00108## 6-[(E)-but-2-enyl]-4-[3- chloro-4-(morpholine-4-
carbonyl)phenyl]-2-methyl- 1H-pyrrolo[2,3-c]pyridin-7- one
##STR00109## 6-but-3-enyl-4-[3-fluoro-5- (morpholine-4-
carbonyl)phenyl]-2-methyl- 1H-pyrrolo[2,3-c]pyridin-7- one
##STR00110## 6-but-3-enyl-4-[4-fluoro-3- (morpholine-4-
carbonyl)phenyl]-2-methyl- 1H-pyrrolo[2,3-c]pyridin-7- one
##STR00111## 6-[(E)-but-2-enyl]-4-[5- chloro-6-(morpholine-4-
carbonyl)-3-pyridyl]-2- methyl-1H-pyrrolo[2,3- c]pyridin-7-one
##STR00112## 6-[(E)-but-2-enyl]-4-[3- chloro-4-(4-methylpiperazine-
1-carbonyl)phenyl]-2-methyl- 1H-pyrrolo[2,3-c]pyridin-7- one
##STR00113## 6-[(E)-but-2-enyl]-2-methyl-4-
[3-methyl-4-(morpholine-4- carbonyl)phenyl]-1H-
pyrrolo[2,3-c]pyridin-7-one ##STR00114## 6-allyl-4-[3-chloro-4-
(morpholine-4- carbonyl)phenyl]-2-methyl-
1H-pyrrolo[2,3-c]pyridin-7- one ##STR00115##
6-allyl-[2,5-dimethoxy-4- (morpholine-4- carbonyl)phenyl]-2-methyl-
1H-pyrrolo[2,3-c]pyridin-7- one ##STR00116##
6-[(E)-but-2-enyl]-4-[3- methoxy-5-(morpholine-4-
carbonyl)-2-pyridyl]-2- methyl-1H-pyrrolo[2,3- c]pyridin-7-one
##STR00117## 6-[(E)-but-2-enyl]-4-[4- chloro-5-(morpholine-4-
carbonyl)-2-pyridyl]-2- methyl-1H-pyrrolo[2,3- c]pyridin-7-one
##STR00118## 6-[(E)-but-2-enyl]-2-methyl-4- [2-(morpholine-4-
carbonyl)pyrimidin-5-yl]-1H- pyrrolo[2,3-c]pyridin-7-one
##STR00119## 5-[6-[(E)-but-2-enyl]-2- methyl-7-oxo-1H-pyrrolo[2,3-
c]pyridin-4-yl]-2-(morpholine- 4-carbonyl)benzonitrile ##STR00120##
6-[(E)-but-2-enyl]-4-[4-(1- hydroxy-1-methyl-ethyl)-2-
methoxy-phenyl]-2-methyl- 1H-pyrrolo[2,3-c]pyridin-7- one
##STR00121## 6-[(E)-but-2-enyl]-4-[2,5- dimethyl-4-(morpholine-4-
carbonyl)phenyl]-2-methyl- 1H-pyrrolo[2,3-c]pyridin-7- one
##STR00122## 3-[6-[(E)-but-2-enyl]-2- methyl-7-oxo-1H-pyrrolo[2,3-
c]pyridin-4-yl]-4-methoxy-N- (pyrazin-2- ylmethyl)benzamide
##STR00123## 6-[(E)-but-2-enyl]-4-[3- methoxy-5-(4-
methylpiperazine-1-carbonyl)- 2-pyridyl]-2-methyl-1H-
pyrrolo[2,3-c]pyridin-7-one ##STR00124## 6-[(E)-but-2-enyl]-4-[6-
chloro-5-(morpholine-4- carbonyl)-2-pyridyl]-2-
methyl-1H-pyrrolo[2,3- c]pyridin-7-one ##STR00125##
1-[4-[6-[(E)-but-2-enyl]-2- methyl-7-oxo-1H-pyrrolo[2,3-
c]pyridin-4-yl]-2-chloro- benzoyl]piperidine-4- carboxylic acid
##STR00126## 1-[4-[6-[(E)-but-2-enyl]-2-
methyl-7-oxo-1H-pyrrolo[2,3- c]pyridin-4-yl]-2-chloro-
benzoyl]piperidine-4- carboxamide ##STR00127##
6-[(E)-but-2-enyl]-4-[3- isopropoxy-4-(morpholine-4-
carbonyl)phenyl]-2-methyl- 1H-pyrrolo[2,3-c]pyridin-7- one
##STR00128## 6-[(E)-but-2-enyl]-4-[3- (cyclopropylmethoxy)-4-
(morpholine-4- carbonyl)phenyl]-2-methyl-
1H-pyrrolo[2,3-c]pyridin-7- one ##STR00129##
6-[(E)-but-2-enyl]-4-[3- chloro-4-(piperazine-1-
carbonyl)phenyl]-2-methyl- 1H-pyrrolo[2,3-c]pyridin-7- one
##STR00130## 4-[4-[3-(3-aminopyrazol-1- yl)azetidine-1-carbonyl]-3-
chloro-phenyl]-6-[(E)-but-2- enyl]-2-methyl-1H-
pyrrolo[2,3-c]pyridin-7-one ##STR00131## 4-[4-[3-(3-aminopyrazol-1-
yl)azetidine-1- carbonyl]phenyl]-6-[(E)-but-2- enyl]-2-methyl-1H-
pyrrolo[2,3-c]pyridin-7-one ##STR00132##
6-[(E)-but-2-enyl]-4-[4-(1- hydroxy-1-methyl-ethyl)-2,5-
dimethoxy-phenyl]-2-methyl- 1H-pyrrolo[2,3-c]pyridin-7- one
##STR00133## 3-[6-[(E)-but-2-enyl]-2- methyl-7-oxo-1H-pyrrolo[2,3-
c]pyridin-4-yl]-4-methoxy-N- (pyrimidin-5- ylmethyl)benzamide
##STR00134## 6-butyl-4-[2,5-dimethoxy-4- (morpholine-4-
carbonyl)phenyl]-2-methyl- 1H-pyrrolo[2,3-c]pyridin-7- one
##STR00135## 6-butyl-4-[3-methoxy-5-(4-
methylpiperazine-1-carbonyl)- 2-pyridyl]-2-methyl-1H-
pyrrolo[2,3-c]pyridin-7-one ##STR00136## 6-butyl-4-[3-methoxy-5-
(morpholine-4-carbonyl)-2- pyridyl]-2-methyl-1H-
pyrrolo[2,3-c]pyridin-7-one
and salts thereof.
In certain embodiments the invention provides compound 1000 as
described in Examples 124 and 126, and salts thereof. The invention
also provides a method for evaluating a compound's ability to
inhibit TAF1-BD2 by monitoring the engagement of compound 1000 with
a TAF1-BD2 target as described in Example 126.
In certain embodiments the invention provides compound 1001 as
described in Examples 125 and 126, and salts thereof. The invention
also provides a method for evaluating a compound's ability to
inhibit CECR2 by monitoring the engagement of compound 1001 with a
CECR2 target as described in Example 126.
Uses, Formulation and Administration
Pharmaceutically Acceptable Compositions
Another aspect includes a pharmaceutical composition comprising a
compound of formula (I) or a pharmaceutically acceptable salt
thereof. In one embodiment, the composition further comprises a
pharmaceutically acceptable carrier, adjuvant, or vehicle. In
another embodiment, the composition further comprises an amount of
the compound effective to measurably inhibit a bromodomain. In
certain embodiments, the composition is formulated for
administration to a patient in need thereof.
The term "patient" or "individual" as used herein, refers to an
animal, such as a mammal, such as a human. In one embodiment,
patient or individual refers to a human.
The term "pharmaceutically acceptable carrier, adjuvant, or
vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that
does not destroy the pharmacological activity of the compound with
which it is formulated. Pharmaceutically acceptable carriers,
adjuvants or vehicles that may be used in the compositions of this
invention include, but are not limited to, ion exchangers, alumina,
aluminum stearate, lecithin, serum proteins, such as human serum
albumin, buffer substances such as phosphates, glycine, sorbic
acid, potassium sorbate, partial glyceride mixtures of saturated
vegetable fatty acids, water, salts or electrolytes, such as
protamine sulfate, disodium hydrogen phosphate, potassium hydrogen
phosphate, sodium chloride, zinc salts, colloidal silica, magnesium
trisilicate, polyvinyl pyrrolidone, cellulose-based substances,
polyethylene glycol, sodium carboxymethylcellulose, polyacrylates,
waxes, polyethylene-polyoxypropylene-block polymers, polyethylene
glycol and wool fat.
Compositions comprising a compound of formula I or salt thereof may
be administered orally, parenterally, by inhalation spray,
topically, transdermally, rectally, nasally, buccally,
sublingually, vaginally, intraperitoneal, intrapulmonary,
intradermal, epidural or via an implanted reservoir. The term
"parenteral" as used herein includes subcutaneous, intravenous,
intramuscular, intra-articular, intra-synovial, intrasternal,
intrathecal, intrahepatic, intralesional and intracranial injection
or infusion techniques.
In one embodiment, the composition comprising a compound of formula
I or salt thereof is formulated as a solid dosage form for oral
administration. Solid dosage forms for oral administration include
capsules, tablets, pills, powders, and granules. In certain
embodiments, the solid oral dosage form comprising a compound of
formula (I) or a salt thereof further comprises one or more of (i)
an inert, pharmaceutically acceptable excipient or carrier, such as
sodium citrate or dicalcium phosphate, and (ii) filler or extender
such as starches, lactose, sucrose, glucose, mannitol, or silicic
acid, (iii) binders such as carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidinone, sucrose or acacia, (iv) humectants
such as glycerol, (v) disintegrating agent such as agar, calcium
carbonate, potato or tapioca starch, alginic acid, certain
silicates or sodium carbonate, (vi) solution retarding agents such
as paraffin, (vii) absorption accelerators such as quaternary
ammonium salts, (viii) a wetting agent such as cetyl alcohol or
glycerol monostearate, (ix) absorbent such as kaolin or bentonite
clay, and (x) lubricant such as talc, calcium stearate, magnesium
stearate, polyethylene glycols or sodium lauryl sulfate. In certain
embodiments, the solid oral dosage form is formulated as capsules,
tablets or pills. In certain embodiments, the solid oral dosage
form further comprises buffering agents. In certain embodiments,
such compositions for solid oral dosage forms may be formulated as
fillers in soft and hard-filled gelatin capsules comprising one or
more excipients such as lactose or milk sugar, polyethylene glycols
and the like.
In certain embodiments, tablets, dragees, capsules, pills and
granules of the compositions comprising a compound of formula I or
salt thereof optionally comprise coatings or shells such as enteric
coatings. They may optionally comprise opacifying agents and can
also be of a composition that they release the active ingredient(s)
only, or preferentially, in a certain part of the intestinal tract,
optionally, in a delayed manner. Examples of embedding compositions
include polymeric substances and waxes, which may also be employed
as fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polethylene glycols and the like.
In another embodiment, a composition comprises micro-encapsulated
compound of formula (I) or salt thereof, and optionally, further
comprises one or more excipients.
In another embodiment, compositions comprise liquid dosage
formulations comprising a compound of formula I or salt thereof for
oral administration, and optionally further comprise one or more of
pharmaceutically acceptable emulsions, microemulsions, solutions,
suspensions, syrups and elixirs. In certain embodiments, the liquid
dosage form optionally, further comprise one or more of an inert
diluent such as water or other solvent, a solubilizing agent, and
an emulsifier such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in
particular, cottonseed, groundnut, corn, germ, olive, castor, and
sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene
glycols or fatty acid esters of sorbitan, and mixtures thereof. In
certain embodiments, liquid oral compositions optionally further
comprise one or more adjuvant, such as a wetting agent, a
suspending agent, a sweetening agent, a flavoring agent and a
perfuming agent.
Injectable preparations, for example, sterile injectable aqueous or
oleaginous suspensions may be formulated according to the known art
using suitable dispersing or wetting agents and suspending agents.
The sterile injectable preparation may also be a sterile injectable
solution, suspension or emulsion in a nontoxic parenterally
acceptable diluent or solvent, for example, as a solution in
1,3-butanediol. Among the acceptable vehicles and solvents that may
be employed are water, Ringer's solution, U.S.P. and isotonic
sodium chloride solution. In addition, sterile, fixed oils are
conventionally employed as a solvent or suspending medium. For this
purpose any bland fixed oil can be employed including synthetic
mono- or diglycerides. In addition, fatty acids such as oleic acid
are used in the preparation of injectables.
Injectable formulations can be sterilized, for example, by
filtration through a bacterial-retaining filter, or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium prior to use.
In order to prolong the effect of a compound of formula (I), it is
often desirable to slow the absorption of the compound from
subcutaneous or intramuscular injection. This may be accomplished
by the use of a liquid suspension of crystalline or amorphous
material with poor water solubility. The rate of absorption of the
compound then depends upon its rate of dissolution that, in turn,
may depend upon crystal size and crystalline form. Alternatively,
delayed absorption of a parenterally administered compound form is
accomplished by dissolving or suspending the compound in an oil
vehicle. Injectable depot forms are made by forming microencapsule
matrices of the compound in biodegradable polymers such as
polylactide-polyglycolide. Depending upon the ratio of compound to
polymer and the nature of the particular polymer employed, the rate
of compound release can be controlled. Examples of other
biodegradable polymers include poly(orthoesters) and
poly(anhydrides). Depot injectable formulations are also prepared
by entrapping the compound in liposomes or microemulsions that are
compatible with body tissues.
In certain embodiments, the composition for rectal or vaginal
administration are formulated as suppositories which can be
prepared by mixing a compound of formula (I) or a salt thereof with
suitable non-irritating excipients or carriers such as cocoa
butter, polyethylene glycol or a suppository wax, for example those
which are solid at ambient temperature but liquid at body
temperature and therefore melt in the rectum or vaginal cavity and
release the compound of formula (I).
Example dosage forms for topical or transdermal administration of a
compound of formula (I) include ointments, pastes, creams, lotions,
gels, powders, solutions, sprays, inhalants or patches. The
compound of formula (I) or a salt thereof is admixed under sterile
conditions with a pharmaceutically acceptable carrier, and
optionally preservatives or buffers. Additional formulation
examples include an ophthalmic formulation, ear drops, eye drops,
transdermal patches. Transdermal dosage forms can be made by
dissolving or dispensing the compound of formula (I) or a salt
thereof in medium, for example ethanol or dimethylsulfoxide.
Absorption enhancers can also be used to increase the flux of the
compound across the skin. The rate can be controlled by either
providing a rate controlling membrane or by dispersing the compound
in a polymer matrix or gel.
Nasal aerosol or inhalation formulations of a compound of formula
(I) or a salt thereof may be prepared as solutions in saline,
employing benzyl alcohol or other suitable preservatives,
absorption promoters to enhance bioavailability, fluorocarbons,
and/or other conventional solubilizing or dispersing agents.
In certain embodiments, pharmaceutical compositions may be
administered with or without food. In certain embodiments,
pharmaceutically acceptable compositions are administered without
food. In certain embodiments, pharmaceutically acceptable
compositions of this invention are administered with food.
Specific dosage and treatment regimen for any particular patient
will depend upon a variety of factors, including age, body weight,
general health, sex, diet, time of administration, rate of
excretion, drug combination, the judgment of the treating
physician, and the severity of the particular disease being
treated. The amount of a provided compound of formula I or salt
thereof in the composition will also depend upon the particular
compound in the composition.
In one embodiment, the therapeutically effective amount of the
compound of the invention administered parenterally per dose will
be in the range of about 0.01-100 mg/kg, alternatively about 0.1 to
20 mg/kg of patient body weight per day, with the typical initial
range of compound used being 0.3 to 15 mg/kg/day. In another
embodiment, oral unit dosage forms, such as tablets and capsules,
contain from about 5 to about 100 mg of the compound of the
invention.
An example tablet oral dosage form comprises about 2 mg, 5 mg, 25
mg, 50 mg, 100 mg, 250 mg or 500 mg of a compound of formula (I) or
salt thereof, and further comprises about 5-30 mg anhydrous
lactose, about 5-40 mg sodium croscarmellose, about 5-30 mg
polyvinylpyrrolidone (PVP) K30 and about 1-10 mg magnesium
stearate. The process of formulating the tablet comprises mixing
the powdered ingredients together and further mixing with a
solution of the PVP. The resulting composition can be dried,
granulated, mixed with the magnesium stearate and compressed to
tablet form using conventional equipment. An example of an aerosol
formulation can be prepared by dissolving about 2-500 mg of a
compound of formula I or salt thereof, in a suitable buffer
solution, e.g. a phosphate buffer, and adding a tonicifier, e.g. a
salt such sodium chloride, if desired. The solution may be
filtered, e.g. using a 0.2 micron filter, to remove impurities and
contaminants.
Uses of Compounds and Pharmaceutically Acceptable Compositions
Another aspect includes the use of a compound of formula (I) or a
salt thereof for the inhibition of a bromodomain (in vitro or in
vivo).
Another embodiment includes a method for treating a
bromodomain-mediated disorder in an animal comprising administering
a compound of formula (I), or a pharmaceutically acceptable salt
thereof to the animal. Bromodomain-mediated disorders include, but
are not limited to those disorders described herein.
Another embodiment includes a method of increasing efficacy of a
cancer treatment comprising a cytotoxic agent in an animal
comprising administering to the animal an effective amount of a
compound of formula (I) or a pharmaceutically acceptable salt
thereof.
Another embodiment includes a method of delaying or preventing
development of cancer resistance to a cytotoxic agent in an animal,
comprising administering to the animal a compound of formula (I) or
a pharmaceutically acceptable salt thereof.
Another embodiment includes a method of extending the duration of
response to a cancer therapy in an animal, comprising administering
to an animal undergoing the cancer therapy a compound of formula
(I) or a pharmaceutically acceptable salt thereof, wherein the
duration of response to the cancer therapy when the compound of
formula (I) or the pharmaceutically acceptable salt thereof is
administered is extended over the duration of response to the
cancer therapy in the absence of the administration of the compound
of formula (I) or the pharmaceutically acceptable salt thereof.
Another embodiment includes a method of treating cancer in an
individual comprising administering to the individual (a) a
compound of formula (I) or a pharmaceutically acceptable salt
thereof, and (b) a cytotoxic agent. In one embodiment the cytotoxic
agent is selected from anti-microtubule agents, platinum
coordination complexes, alkylating agents, antibiotic agents,
topoisomerase II inhibitors, antimetabolites, topoisomerase I
inhibitors, hormones and hormonal analogues, signal transduction
pathway inhibitors, non-receptor tyrosine kinase angiogenesis
inhibitors, immunotherapeutic agents, proapoptotic agents,
inhibitors of LDH-A, inhibitors of fatty acid biosynthesis, cell
cycle signaling inhibitors, HDAC inhibitors, proteasome inhibitors,
and inhibitors of cancer metabolism. In one embodiment the
cytotoxic agent is a taxane. In one embodiment the taxane is
paclitaxel or docetaxel. In one embodiment the cytotoxic agent is a
platinum agent. In one embodiment the cytotoxic agent is an
antagonist of EGFR. In one embodiment the antagonist of EGFR is
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine or a
pharmaceutically acceptable salt thereof (e.g., erlotinib). In one
embodiment the cytotoxic agent is a RAF inhibitor. In one
embodiment the RAF inhibitor is a BRAF or CRAF inhibitor. In one
embodiment the RAF inhibitor is vemurafenib. In one embodiment the
cytotoxic agent is a PI3K inhibitor.
In certain embodiments, treatment may be administered after one or
more symptoms have developed. In other embodiments, treatment may
be administered in the absence of symptoms. For example, treatment
may be administered to a susceptible individual prior to the onset
of symptoms (e.g., in light of a history of symptoms and/or in
light of genetic or other susceptibility factors). Treatment may
also be continued after symptoms have resolved, for example to
prevent or delay their recurrence.
Bromodomain-Mediated Disorders
A "bromodomain-mediated disorder" is characterized by the
participation of one or more bromodomains (e.g., BRD4) in the
inception, manifestation of one or more symptoms or disease
markers, severity, or progression of a disorder. Bromodomains
include, but are not limited to ASH1L, ATAD2, ATAD2B, BAZ1A, BAZ1B,
BAZ2A, BAZ2B, BPTF, BRD1, BRD2, BRD3, BRD4, BRD7, BRD8, BRD9, BRDT,
BRPF1, BRPF3, BRWD1, BRWD3, CECR2, CREBBP (aka, CBP), EP300,
GCN5L2, KIAA2026, MLL, MLL4, PBRM, PCAF, PHIP, SMARCA2, SMARCA4,
SP100, SP110, SP140, SP140L, TAF1, TAF1L, TRIM24, TRIM28, TRIM33,
TRIM66, ZMYND8, and ZMYND11.
Bromodomain-mediated disorders include cancers, including, but not
limited to acoustic neuroma, acute leukemia, acute lymphocytic
leukemia, acute myelocytic leukemia (monocytic, myeloblastic,
adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and
promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile
duct carcinoma, bladder cancer, brain cancer, breast cancer,
bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma,
choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia,
chronic myelocytic (granulocytic) leukemia, chronic myelogenous
leukemia, colon cancer, colorectal cancer, craniopharyngioma,
cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative
changes (dysplasias and metaplasias), embryonal carcinoma,
endometrial cancer, endotheliosarcoma, ependymoma, epithelial
carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor
positive breast cancer, essential thrombocythemia, Ewing's tumor,
fibrosarcoma, follicular lymphoma, germ cell testicular cancer,
glioma, glioblastoma, gliosarcoma, heavy chain disease,
hemangioblastoma, hepatoma, hepatocellular cancer, hormone
insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma,
lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma,
lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's),
malignancies and hyperproliferative disorders of the bladder,
breast, colon, lung, ovaries, pancreas, prostate, skin and uterus,
lymphoid malignancies of T-cell or B-cell origin, medullary
carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma,
multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma,
neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung
cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian
cancer, pancreatic cancer, papillary adenocarcinomas, papillary
carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal
cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma,
sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small
cell lung carcinoma, solid tumors (carcinomas and sarcomas), small
cell lung cancer, stomach cancer, squamous cell carcinoma,
synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's
macroglobulinemia, testicular tumors, uterine cancer and Wilms'
tumor.
In certain embodiments, the cancer is lung cancer, breast cancer,
pancreatic cancer, colorectal cancer, and/or melanoma. In certain
embodiments, the cancer is lung. In certain embodiments, the lung
cancer is NSCLC. In certain embodiments, the cancer is breast
cancer. In certain embodiments, the cancer is melanoma.
Bromodomain-mediated disorders also include inflammatory diseases,
inflammatory conditions, and autoimmune diseases, including, but
not limited to: Addison's disease, acute gout, ankylosing
spondylitis, asthma, atherosclerosis, Behcet's disease, bullous
skin diseases, chronic obstructive pulmonary disease (COPD),
Crohn's disease, dermatitis, eczema, giant cell arteritis,
glomerulonephritis, hepatitis, hypophysitis, inflammatory bowel
disease, Kawasaki disease, lupus nephritis, multiple sclerosis,
myocarditis, myositis, nephritis, organ transplant rejection,
osteoarthritis, pancreatitis, pericarditis, Polyarteritis nodosa,
pneumonitis, primary biliary cirrhosis, psoriasis, psoriatic
arthritis, rheumatoid arthritis, scleritis, sclerosing cholangitis,
sepsis, systemic lupus erythematosus, Takayasu's Arteritis, toxic
shock, thyroiditis, type I diabetes, ulcerative colitis, uveitis,
vitiligo, vasculitis, and Wegener's granulomatosis.
Bromodomain-mediated disorders also include AIDS; chronic kidney
diseases, including, but are not limited to diabetic nephropathy,
hypertensive nephropathy, HIV-associated nephropathy,
glomerulonephritis, lupus nephritis, IgA nephropathy, focal
segmental glomerulosclerosis, membranous glomerulonephritis,
minimal change disease, polycystic kidney disease and tubular
interstitial nephritis; acute kidney injury or disease or condition
including, but are not limited to ischemia-reperfusion induced,
cardiac and major surgery induced, percutaneous coronary
intervention induced, radio-contrast agent induced, sepsis induced,
pneumonia induced, and drug toxicity induced; obesity;
dyslipidemia; hypercholesterolemia; Alzheimer's disease; metabolic
syndrome; hepatic steatosis; type II diabetes; insulin resistance;
and diabetic retinopathy.
Bromodomain inhibitors may also be used to provide male
contraception.
Co-Administration of Compounds and Other Agents
The compounds of formula (I) or salts thereof may be employed alone
or in combination with other agents for treatment. For example, the
second agent of the pharmaceutical combination formulation or
dosing regimen may have complementary activities to the compound of
formula (I) such that they do not adversely affect each other. The
compounds may be administered together in a unitary pharmaceutical
composition or separately. In one embodiment a compound or a
pharmaceutically acceptable salt can be co-administered with a
cytotoxic agent to treat proliferative diseases and cancer.
The term "co-administering" refers to either simultaneous
administration, or any manner of separate sequential
administration, of a compound of formula (I) or a salt thereof, and
a further active pharmaceutical ingredient or ingredients,
including cytotoxic agents and radiation treatment. If the
administration is not simultaneous, the compounds are administered
in a close time proximity to each other. Furthermore, it does not
matter if the compounds are administered in the same dosage form,
e.g. one compound may be administered topically and another
compound may be administered orally.
Typically, any agent that has activity against a disease or
condition being treated may be co-administered. Examples of such
agents can be found in Cancer Principles and Practice of Oncology
by V. T. Devita and S. Hellman (editors), 6.sup.th edition (Feb.
15, 2001), Lippincott Williams & Wilkins Publishers. A person
of ordinary skill in the art would be able to discern which
combinations of agents would be useful based on the particular
characteristics of the drugs and the disease involved.
In one embodiment, the treatment method includes the
co-administration of a compound of formula (I) or a
pharmaceutically acceptable salt thereof and at least one cytotoxic
agent. The term "cytotoxic agent" as used herein refers to a
substance that inhibits or prevents a cellular function and/or
causes cell death or destruction. Cytotoxic agents include, but are
not limited to, radioactive isotopes (e.g., At.sup.211, I.sup.131,
I.sup.125, Y.sup.90, Re.sup.186, Re.sup.188, Sm.sup.153,
Bi.sup.212, P.sup.32, Pb.sup.212 and radioactive isotopes of Lu);
chemotherapeutic agents; growth inhibitory agents; enzymes and
fragments thereof such as nucleolytic enzymes; and toxins such as
small molecule toxins or enzymatically active toxins of bacterial,
fungal, plant or animal origin, including fragments and/or variants
thereof.
Exemplary cytotoxic agents can be selected from anti-microtubule
agents, platinum coordination complexes, alkylating agents,
antibiotic agents, topoisomerase II inhibitors, antimetabolites,
topoisomerase I inhibitors, hormones and hormonal analogues, signal
transduction pathway inhibitors, non-receptor tyrosine kinase
angiogenesis inhibitors, immunotherapeutic agents, proapoptotic
agents, inhibitors of LDH-A; inhibitors of fatty acid biosynthesis;
cell cycle signaling inhibitors; HDAC inhibitors, proteasome
inhibitors; and inhibitors of cancer metabolism.
"Chemotherapeutic agent" includes chemical compounds useful in the
treatment of cancer. Examples of chemotherapeutic agents include
erlotinib (TARCEVA.RTM., Genentech/OSI Pharm.), bortezomib
(VELCADE.RTM., Millennium Pharm.), disulfiram, epigallocatechin
gallate, salinosporamide A, carfilzomib, 17-AAG(geldanamycin),
radicicol, lactate dehydrogenase A (LDH-A), fulvestrant
(FASLODEX.RTM., Astra7eneca), sunitib (SUTENT.RTM., Pfizer/Sugen),
letrozole (FEMARA.RTM., Novartis), imatinib mesylate (GLEEVEC.RTM.,
Novartis), finasunate (VATALANIB.RTM., Novartis), oxaliplatin
(ELOXATIN.RTM., Sanofi), 5-FU (5-fluorouracil), leucovorin,
Rapamycin (Sirolimus, RAPAMUNE.RTM., Wyeth), Lapatinib
(TYKERB.RTM., GSK572016, Glaxo Smith Kline), Lonafamib (SCH 66336),
sorafenib (NEXAVAR.RTM., Bayer Labs), gefitinib (IRESSA.RTM.,
AstraZeneca), AG1478, alkylating agents such as thiotepa and
CYTOXAN.RTM. cyclosphosphamide; alkyl sulfonates such as busulfan,
improsulfan and piposulfan; aziridines such as benzodopa,
carboquone, meturedopa, and uredopa; ethylenimines and
methylamelamines including altretamine, triethylenemelamine,
triethylenephosphoramide, triethylenethiophosphoramide and
trimethylomelamine; acetogenins (especially bullatacin and
bullatacinone); a camptothecin (including topotecan and
irinotecan); bryostatin; callystatin; CC-1065 (including its
adozelesin, carzelesin and bizelesin synthetic analogs);
cryptophycins (particularly cryptophycin 1 and cryptophycin 8);
adrenocorticosteroids (including prednisone and prednisolone);
cyproterone acetate; 5.alpha.-reductases including finasteride and
dutasteride); vorinostat, romidepsin, panobinostat, valproic acid,
mocetinostat dolastatin; aldesleukin, talc duocarmycin (including
the synthetic analogs, KW-2189 and CB1-TM1); eleutherobin;
pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards
such as chlorambucil, chlomaphazine, chlorophosphamide,
estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide
hydrochloride, melphalan, novembichin, phenesterine, prednimustine,
trofosfamide, uracil mustard; nitrosoureas such as carmustine,
chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine;
antibiotics such as the enediyne antibiotics (e.g., calicheamicin,
especially calicheamicin .gamma.1I and calicheamicin .omega.1I
(Angew Chem. Intl. Ed. Engl. 1994 33:183-186); dynemicin, including
dynemicin A; bisphosphonates, such as clodronate; an esperamicin;
as well as neocarzinostatin chromophore and related chromoprotein
enediyne antibiotic chromophores), aclacinomysins, actinomycin,
authramycin, azaserine, bleomycins, cactinomycin, carabicin,
caminomycin, carzinophilin, chromomycinis, dactinomycin,
daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine,
ADRIAMYCIN.RTM. (doxorubicin), morpholino-doxorubicin,
cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and
deoxydoxorubicin), epirubicin, esorubicin, idarubicin,
marcellomycin, mitomycins such as mitomycin C, mycophenolic acid,
nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin,
quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,
ubenimex, zinostatin, zorubicin; anti-metabolites such as
methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as
denopterin, methotrexate, pteropterin, trimetrexate; purine analogs
such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine;
pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine,
carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine,
floxuridine; androgens such as calusterone, dromostanolone
propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals
such as aminoglutethimide, mitotane, trilostane; folic acid
replenisher such as frolinic acid; aceglatone; aldophosphamide
glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil;
bisantrene; edatraxate; defofamine; demecolcine; diaziquone;
elfomithine; elliptinium acetate; an epothilone; etoglucid; gallium
nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as
maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamnol;
nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone;
podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK.RTM.
polysaccharide complex (JHS Natural Products, Eugene, Oreg.);
razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid;
triaziquone; 2,2',2''-trichlorotriethylamine; trichothecenes
(especially T-2 toxin, verracurin A, roridin A and anguidine);
urethan; vindesine; dacarbazine; mannomustine; mitobronitol;
mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C");
cyclophosphamide; thiotepa; taxoids, e.g., TAXOL (paclitaxel;
Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE.RTM.
(Cremophor-free), albumin-engineered nanoparticle formulations of
paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.),
and TAXOTERE.RTM. (docetaxel, doxetaxel; Sanofi-Aventis);
chloranmbucil; GEMZAR.RTM. (gemcitabine); 6-thioguanine;
mercaptopurine; methotrexate; platinum analogs such as cisplatin
and carboplatin; vinblastine; etoposide (VP-16); ifosfamide;
mitoxantrone; vincristine; NAVELBINE.RTM. (vinorelbine);
novantrone; teniposide; edatrexate; daunomycin; aminopterin;
capecitabine (XELODA.RTM.); ibandronate; CPT-11; topoisomerase
inhibitor RFS 2000; difluoromethylomithine (DMFO); retinoids such
as retinoic acid; and pharmaceutically acceptable salts, acids and
derivatives of any of the above.
Chemotherapeutic agent also includes (i) anti-hormonal agents that
act to regulate or inhibit hormone action on tumors such as
anti-estrogens and selective estrogen receptor modulators (SERMs),
including, for example, tamoxifen (including NOLVADEX.RTM.;
tamoxifen citrate), raloxifene, droloxifene, iodoxyfene,
4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone,
and FARESTON.RTM. (toremifine citrate); (ii) aromatase inhibitors
that inhibit the enzyme aromatase, which regulates estrogen
production in the adrenal glands, such as, for example,
4(5)-imidazoles, aminoglutethimide, MEGASE.RTM. (megestrol
acetate), AROMASIN.RTM. (exemestane; Pfizer), formestanie,
fadrozole, RIVISOR.RTM. (vorozole), FEMARA.RTM. (letrozole;
Novartis), and ARIMIDEX.RTM. (anastrozole; AstraZeneca); (iii)
anti-androgens such as flutamide, nilutamide, bicalutamide,
leuprolide and goserelin; buserelin, tripterelin,
medroxyprogesterone acetate, diethylstilbestrol, premarin,
fluoxymesterone, all transretionic acid, fenretinide, as well as
troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv)
protein kinase inhibitors; (v) lipid kinase inhibitors; (vi)
antisense oligonucleotides, particularly those which inhibit
expression of genes in signaling pathways implicated in aberrant
cell proliferation, such as, for example, PKC-alpha, Ralf and
H-Ras; (vii) ribozymes such as VEGF expression inhibitors (e.g.,
ANGIOZYME.RTM.) and HER2 expression inhibitors; (viii) vaccines
such as gene therapy vaccines, for example, ALLOVECTIN.RTM.,
LEUVECTIN.RTM., and VAXID.RTM.; PROLEUKIN.RTM., rIL-2; a
topoisomerase 1 inhibitor such as LURTOTECAN.RTM.; ABARELIX.RTM.
rmRH; and (ix) pharmaceutically acceptable salts, acids and
derivatives of any of the above.
Chemotherapeutic agent also includes antibodies such as alemtuzumab
(Campath), bevacizumab (AVASTIN.RTM., Genentech); cetuximab
(ERBITUX.RTM., Imclone); panitumumab (VECTIBIX.RTM., Amgen),
rituximab (RITUXAN.RTM., Genentech/Biogen Idec), pertuzumab
(OMNITARG.RTM., 2C4, Genentech), trastuzumab (HERCEPTIN.RTM.,
Genentech), tositumomab (Bexxar, Corixia), and the antibody drug
conjugate, gemtuzumab ozogamicin (MYLOTARG.RTM., Wyeth). Additional
humanized monoclonal antibodies with therapeutic potential as
agents in combination with the compounds of the invention include:
apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab
mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol,
cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab,
epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab
ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab,
lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab,
natalizumab, nimotuzumab, nolovizumab, numavizumab, ocrelizumab,
omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab,
pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab,
resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab,
sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab,
tefibazumab, tocilizumab, toralizumab, tucotuzumab celmoleukin,
tucusituzumab, umavizumab, urtoxazumab, ustekinumab, visilizumab,
and the anti interleukin-12 (ABT-8744695, Wyeth Research and Abbott
Laboratories) which is a recombinant exclusively human-sequence,
full-length IgG.sub.1 .lamda. antibody genetically modified to
recognize interleukin-12 p40 protein.
Chemotherapeutic agent also includes "EGFR inhibitors," which
refers to compounds that bind to or otherwise interact directly
with EGFR and prevent or reduce its signaling activity, and is
alternatively referred to as an "EGFR antagonist." Examples of such
agents include antibodies and small molecules that bind to EGFR.
Examples of antibodies which bind to EGFR include MAb 579 (ATCC CRL
HB 8506), MAb 455 (ATCC CRL HB8507), MAb 225 (ATCC CRL 8508), MAb
528 (ATCC CRL 8509) (see, U.S. Pat. No. 4,943,533, Mendelsohn et
al.) and variants thereof, such as chimerized 225 (C225 or
Cetuximab; ERBUTIX.RTM.) and reshaped human 225 (H225) (see, WO
96/40210, Imclone Systems Inc.); IMC-11F8, a fully human,
EGFR-targeted antibody (Imclone); antibodies that bind type II
mutant EGFR (U.S. Pat. No. 5,212,290); humanized and chimeric
antibodies that bind EGFR as described in U.S. Pat. No. 5,891,996;
and human antibodies that bind EGFR, such as ABX-EGF or Panitumumab
(see WO98/50433, Abgenix/Amgen); EMD 55900 (Stragliotto et al. Eur.
J. Cancer 32A:636-640 (1996)); EMD7200 (matuzumab) a humanized EGFR
antibody directed against EGFR that competes with both EGF and
TGF-alpha for EGFR binding (EMD/Merck); human EGFR antibody,
HuMax-EGFR (GenMab); fully human antibodies known as E1.1, E2.4,
E2.5, E6.2, E6.4, E2.11, E6. 3 and E7.6. 3 and described in U.S.
Pat. No. 6,235,883; MDX-447 (Medarex Inc); and mAb 806 or humanized
mAb 806 (Johns et al., J. Biol. Chem. 279(29):30375-30384 (2004)).
The anti-EGFR antibody may be conjugated with a cytotoxic agent,
thus generating an immunoconjugate (see, e.g., EP659,439A2, Merck
Patent GmbH). EGFR antagonists include small molecules such as
compounds described in U.S. Pat. Nos. 5,616,582, 5,457,105,
5,475,001, 5,654,307, 5,679,683, 6,084,095, 6,265,410, 6,455,534,
6,521,620, 6,596,726, 6,713,484, 5,770,599, 6,140,332, 5,866,572,
6,399,602, 6,344,459, 6,602,863, 6,391,874, 6,344,455, 5,760,041,
6,002,008, and 5,747,498, as well as the following PCT
publications: WO98/14451, WO98/50038, WO99/09016, and WO99/24037.
Particular small molecule EGFR antagonists include OSI-774
(CP-358774, erlotinib, TARCEVA.RTM. Genentech/OSI Pharmaceuticals);
PD 183805 (CI 1033, 2-propenamide,
N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quin-
azolinyl]-, dihydrochloride, Pfizer Inc.); ZD1839, gefitinib
(IRESSA.RTM.)
4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoli-
ne, AstraZeneca); ZM 105180
((6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca); BIBX-1382
(N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methyl-piperidin-4-yl)-pyrimido[5,4--
d]pyrimidine-2,8-diamine, Boehringer Ingelheim); PKI-166
((R)-4-[4-[(1-phenylethyl)amino]-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol)-
;
(R)-6-(4-hydroxyphenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimi-
dine); CL-387785
(N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide); EKB-569
(N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxy-6-quinolinyl]-4-(-
dimethylamino)-2-butenamide) (Wyeth); AG1478 (Pfizer); AG1571 (SU
5271; Pfizer); dual EGFR/HER2 tyrosine kinase inhibitors such as
lapatinib (TYKERB.RTM., GSK572016 or N-[3-chloro-4-[(3
fluorophenyl)methoxy]phenyl]-6[5[[[2methylsulfonyl)ethyl]amino]methyl]-2--
furanyl]-4-quinazolinamine).
Chemotherapeutic agents also include "tyrosine kinase inhibitors"
including the EGFR-targeted drugs noted in the preceding paragraph;
small molecule HER2 tyrosine kinase inhibitor such as TAK165
available from Takeda; CP-724,714, an oral selective inhibitor of
the ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual-HER
inhibitors such as EKB-569 (available from Wyeth) which
preferentially binds EGFR but inhibits both HER2 and
EGFR-overexpressing cells; lapatinib (GSK572016; available from
Glaxo-SmithKline), an oral HER2 and EGFR tyrosine kinase inhibitor;
PKI-166 (available from Novartis); pan-HER inhibitors such as
canertinib (CI-1033; Pharmacia); Raf-1 inhibitors such as antisense
agent ISIS-5132 available from ISIS Pharmaceuticals which inhibit
Raf-1 signaling; non-HER targeted TK inhibitors such as imatinib
mesylate (GLEEVEC.RTM., available from Glaxo SmithKline);
multi-targeted tyrosine kinase inhibitors such as sunitinib
(SUTENT.RTM., available from Pfizer); VEGF receptor tyrosine kinase
inhibitors such as vatalanib (PTK787/ZK222584, available from
Novartis/Schering AG); MAPK extracellular regulated kinase 1
inhibitor CI-1040 (available from Pharmacia); quinazolines, such as
PD 153035,4-(3-chloroanilino) quinazoline; pyridopyrimidines;
pyrimidopyrimidines; pyrrolopyrimidines, such as CGP 59326, CGP
60261 and CGP 62706; pyrazolopyrimidines,
4-(phenylamino)-7H-pyrrolo[2,3-d] pyrimidines; curcumin (diferuloyl
methane, 4,5-bis (4-fluoroanilino)phthalimide); tyrphostines
containing nitrothiophene moieties; PD-0183805 (Warner-Lamber);
antisense molecules (e.g. those that bind to HER-encoding nucleic
acid); quinoxalines (U.S. Pat. No. 5,804,396); tryphostins (U.S.
Pat. No. 5,804,396); ZD6474 (Astra Zeneca); PTK-787
(Novartis/Schering AG); pan-HER inhibitors such as CI-1033
(Pfizer); Affinitac (ISIS 3521; Isis/Lilly); imatinib mesylate
(GLEEVEC.RTM.); PKI 166 (Novartis); GW2016 (Glaxo SmithKline);
CI-1033 (Pfizer); EKB-569 (Wyeth); Semaxinib (Pfizer); ZD6474
(AstraZeneca); PTK-787 (Novartis/Schering AG); INC-1C11 (Imclone),
rapamycin (sirolimus, RAPAMUNE.RTM.); or as described in any of the
following patent publications: U.S. Pat. No. 5,804,396; WO
1999/09016 (American Cyanamid); WO 1998/43960 (American Cyanamid);
WO 1997/38983 (Warner Lambert); WO 1999/06378 (Warner Lambert); WO
1999/06396 (Warner Lambert); WO 1996/30347 (Pfizer, Inc); WO
1996/33978 (Zeneca); WO 1996/3397 (Zeneca) and WO 1996/33980
(Zeneca).
Chemotherapeutic agents also include dexamethasone, interferons,
colchicine, metoprine, cyclosporine, amphotericin, metronidazole,
alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic
trioxide, asparaginase, BCG live, bevacuzimab, bexarotene,
cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane,
epoetin alfa, elotinib, filgrastim, histrelin acetate, ibritumomab,
interferon alfa-2a, interferon alfa-2b, lenalidomide, levamisole,
mesna, methoxsalen, nandrolone, nelarabine, nofetumomab,
oprelvekin, palifermin, pamidronate, pegademase, pegaspargase,
pegfilgrastim, pemetrexed disodium, plicamycin, porfimer sodium,
quinacrine, rasburicase, sargramostim, temozolomide, VM-26, 6-TG,
toremifene, tretinoin, ATRA, valrubicin, zoledronate, and
zoledronic acid, and pharmaceutically acceptable salts thereof.
Chemotherapeutic agents also include hydrocortisone, hydrocortisone
acetate, cortisone acetate, tixocortol pivalate, triamcinolone
acetonide, triamcinolone alcohol, mometasone, amcinonide,
budesonide, desonide, fluocinonide, fluocinolone acetonide,
betamethasone, betamethasone sodium phosphate, dexamethasone,
dexamethasone sodium phosphate, fluocortolone,
hydrocortisone-17-butyrate, hydrocortisone-17-valerate,
aclometasone dipropionate, betamethasone valerate, betamethasone
dipropionate, prednicarbate, clobetasone-17-butyrate,
clobetasol-17-propionate, fluocortolone caproate, fluocortolone
pivalate and fluprednidene acetate; immune selective
anti-inflammatory peptides (ImSAIDs) such as
phenylalanine-glutamine-glycine (FEG) and its D-isomeric form (feG)
(IMULAN BioTherapeutics, LLC); anti-rheumatic drugs such as
azathioprine, ciclosporin (cyclosporine A), D-penicillamine, gold
salts, hydroxychloroquine, leflunomideminocycline, sulfasalazine,
tumor necrosis factor alpha (TNF.alpha.) blockers such as
etanercept (Enbrel), infliximab (Remicade), adalimumab (1-Iumira),
certolizumab pegol (Cimzia), golimumab (Simponi), Interleukin 1
(IL-1) blockers such as anakinra (Kineret), T cell costimulation
blockers such as abatacept (Orencia), Interleukin 6 (IL-6) blockers
such as tocilizumab (ACTEMERA.RTM.); Interleukin 13 (IL-13)
blockers such as lebrikizumab; Interferon alpha (IFN) blockers such
as Rontalizumab; Beta 7 integrin blockers such as rhuMAb Beta7; IgE
pathway blockers such as Anti-M1 prime; Secreted homotrimeric LTa3
and membrane bound heterotrimer LTa1/132 blockers such as
Anti-lymphotoxin alpha (LTa); radioactive isotopes (e.g.,
At.sup.211, I.sup.131, I.sup.125, Y.sup.90, Re.sup.186, Re.sup.188,
Sm.sup.153, Bi.sup.212, P.sup.32, Pb.sup.212 and radioactive
isotopes of Lu); miscellaneous investigational agents such as
thioplatin, PS-341, phenylbutyrate, ET-18-OCH.sub.3, or famesyl
transferase inhibitors (L-739749, L-744832); polyphenols such as
quercetin, resveratrol, piceatannol, epigallocatechine gallate,
theaflavins, flavanols, procyanidins, betulinic acid and
derivatives thereof; autophagy inhibitors such as chloroquine;
delta-9-tetrahydrocannabinol (dronabinol, MARINOL.RTM.);
beta-lapachone; lapachol; colchicines; betulinic acid;
acetylcamptothecin, scopolectin, and 9-aminocamptothecin);
podophyllotoxin; tegafur (UFTORAL.RTM.); bexarotene
(TARGRETIN.RTM.); bisphosphonates such as clodronate (for example,
BONEFOS.RTM. or OSTAC.RTM.), etidronate (DIDROCAL.RTM.), NE-58095,
zoledronic acid/zoledronate (ZOMETA0), alendronate (FOSAMAX.RTM.),
pamidronate (AREDIA.RTM.), tiludronate (SKELID.RTM.), or
risedronate (ACTONEL.RTM.); and epidermal growth factor receptor
(EGF-R); vaccines such as THERATOPE.RTM. vaccine; perifosine, COX-2
inhibitor (e.g. celecoxib or etoricoxib), proteosome inhibitor
(e.g. PS341); CCI-779; tipifarnib (R11577); orafenib, ABT510; Bcl-2
inhibitor such as oblimersen sodium (GENASENSE.RTM.); pixantrone;
farnesyltransferase inhibitors such as lonafamib (SCH 6636,
SARASAR.TM.); and pharmaceutically acceptable salts, acids or
derivatives of any of the above; as well as combinations of two or
more of the above such as CHOP, an abbreviation for a combined
therapy of cyclophosphamide, doxorubicin, vincristine, and
prednisolone; and FOLFOX, an abbreviation for a treatment regimen
with oxaliplatin (ELOXATIN.TM.) combined with 5-FU and
leucovorin.
Chemotherapeutic agents also include non-steroidal
anti-inflammatory drugs with analgesic, antipyretic and
anti-inflammatory effects. NSAIDs include non-selective inhibitors
of the enzyme cyclooxygenase. Specific examples of NSAIDs include
aspirin, propionic acid derivatives such as ibuprofen, fenoprofen,
ketoprofen, flurbiprofen, oxaprozin and naproxen, acetic acid
derivatives such as indomethacin, sulindac, etodolac, diclofenac,
enolic acid derivatives such as piroxicam, meloxicam, tenoxicam,
droxicam, lornoxicam and isoxicam, fenamic acid derivatives such as
mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic
acid, and COX-2 inhibitors such as celecoxib, etoricoxib,
lumiracoxib, parecoxib, rofecoxib, rofecoxib, and valdecoxib.
NSAIDs can be indicated for the symptomatic relief of conditions
such as rheumatoid arthritis, osteoarthritis, inflammatory
arthropathies, ankylosing spondylitis, psoriatic arthritis,
Reiter's syndrome, acute gout, dysmenorrhoea, metastatic bone pain,
headache and migraine, postoperative pain, mild-to-moderate pain
due to inflammation and tissue injury, pyrexia, ileus, and renal
colic.
Chemotherapeutic agents also include treatments for Alzheimer's
Disease such as donepezil hydrochloride and rivastigmine;
treatments for Parkinson's Disease such as L-DOPA/carbidopa,
entacapone, ropinrole, pramipexole, bromocriptine, pergolide,
trihexephendyl, and amantadine; agents for treating multiple
sclerosis (MS) such as beta interferon (e.g., Avonex.RTM. and
Rebid.RTM.), glatiramer acetate, and mitoxantrone; treatments for
asthma such as albuterol and montelukast sodium; agents for
treating schizophrenia such as zyprexa, risperdal, seroquel, and
haloperidol; anti-inflammatory agents such as corticosteroids, TNF
blockers, IL-1 RA, azathioprine, cyclophosphamide, and
sulfasalazine; immunomodulatory and immunosuppressive agents such
as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil,
interferons, corticosteroids, cyclophophamide, azathioprine, and
sulfasalazine; neurotrophic factors such as acetylcholinesterase
inhibitors, MAO inhibitors, interferons, anti-convulsants, ion
channel blockers, riluzole, and anti-Parkinsonian agents; agents
for treating cardiovascular disease such as beta-blockers, ACE
inhibitors, diuretics, nitrates, calcium channel blockers, and
statins; agents for treating liver disease such as corticosteroids,
cholestyramine, interferons, and anti-viral agents; agents for
treating blood disorders such as corticosteroids, anti-leukemic
agents, and growth factors; and agents for treating
immunodeficiency disorders such as gamma globulin.
Additionally, chemotherapeutic agents include pharmaceutically
acceptable salts, acids or derivatives of any of chemotherapeutic
agents, described herein, as well as combinations of two or more of
them.
For treating an inflammatory disease or an autoimmune disease, a
compound of formula (I) or a pharmaceutically acceptable salt
thereof may be co-administered with methotrexate, tofacitinib,
6-mercaptopurine, azathioprine sulphasalazine, mesalazine,
olsalazine chloroquinine/hydroxychloroquinine, penicillamine,
aurothiomalate (intramuscular and oral), azathioprine, cochicine,
corticosteroids (oral, inhaled, and local injection), a beta-2
adrenoreceptor agonist (salbutamol, terbutaline, salmeteral), a
xanthine (theophylline, aminophylline), cromoglycate, nedocromil,
ketotifen, ipratropium and oxitropium, cyclosporin, FK506,
rapamycin, mycophenolate mofetil, leflunomide, an NSAID (e.g.
ibuprofen), a corticosteroid (e. g. prednisolone), a
phosphodiesterase inhibitor, an adenosine agonist, an
antithrombotic agent, a complement inhibitor, an adrenergic agent,
an agent that interferes with signalling by proinflammatory
cytokines such as TNF or IL-1 (e.g., a NIK, IKK, p38 or MAP kinase
inhibitor), an IL-1 converting enzyme inhibitor, a T-cell
signalling inhibitor (e.g. a kinase inhibitor), a metalloproteinase
inhibitor, sulfasalazine, a 6-mercaptopurine, an angiotensin
converting enzyme inhibitor, a soluble cytokine receptor (e.g.
soluble p55 or p75 TNF receptors and the derivatives p75TNFRigG
(etanercept) and p55TNFRigG (Lenercept), siL-lRI, siL-lRII,
siL-6R), an antiinflammatory cytokine (e.g. IL-4, IL-10, IL-11,
IL-13 and TGF), celecoxib, folic acid, hydroxychloroquine sulfate,
rofecoxib, etanercept, infliximab, adalimumab, certolizumab,
tocilizumab, abatacept, naproxen, valdecoxib, sulfasalazine,
methylprednisolone, meloxicam, methylprednisolone acetate, gold
sodium thiomalate, aspirin, triamcinolone acetonide, propoxyphene
napsylate/apap, folate, nabumetone, diclofenac, piroxicam,
etodolac, diclofenac sodium, oxaprozin, oxycodone HCl, hydrocodone
bitartrate/apap, diclofenac sodium/misoprostol, fentanyl, anakinra,
tramadol HCl, salsalate, sulindac, cyanocobalamin/fa/pyridoxine,
acetaminophen, alendronate sodium, prednisolone, cortisone,
betamethasone, morphine sulfate, lidocaine hydrochloride,
indomethacin, glucosamine sulf/chondroitin, amitriptyline HCl,
sulfadiazine, oxycodone HCVacetaminophen, olopatadine HCl
misoprostol, naproxen sodium, omeprazole, cyclophosphamide,
rituximab, IL-1 TRAP, MRA, CTLA4-IG, IL-18 BP, anti-IL-12,
Anti-IL1S, BIRB-796, SCIO-469, VX-702, AMG-548, VX-740,
Roflumilast, IC-485, CDC-801, SIP1 agonists (such as FTY720), a PKC
family inhibitor (e.g. Ruboxistaurin or AES-071) or Mesopram. In
certain embodiments, a compound of formula (I) or a
pharmaceutically acceptable salt thereof may be co-administered
with methotrexate or leflunomide. In moderate or severe rheumatoid
arthritis cases, a compound of formula (I) or a pharmaceutically
acceptable salt thereof may be co-administered with cyclosporine
and anti-TNF antibodies as noted above. A compound of formula (I)
or a pharmaceutically acceptable salt thereof may also be
co-administered with: budenoside; epidermal growth factor; a
corticosteroid; cyclosporin, sulfasalazine; an aminosalicylate;
6-mercaptopurine; azathioprine; metronidazole; a lipoxygenase
inhibitor; mesalamine; olsalazine; balsalazide; an antioxidant; a
thromboxane inhibitor; an IL-1 receptor antagonist; an anti-IL-1
monoclonal antibody; an anti-IL-6 monoclonal antibody; a growth
factor; an elastase inhibitor; a pyridinyl-imidazole compound; an
antibody to or antagonist of other human cytokines or growth
factors (e.g. TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-15,
IL-16, IL-23, EMAP-II, GM-CSF, FGF, and PDGF); a cell surface
molecule (e.g. CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45,
CD69, or CD90 or their ligands); methotrexate; cyclosporine; FK506;
rapamycin; mycophenolate mofetil; leflunomide; an NSAID (e.g.
ibuprofen); a corticosteroid (e.g. prednisolone); a
phosphodiesterase inhibitor; an adenosine agonist; an
antithrombotic agent; a complement inhibitor; an adrenergic agent;
an agent that interferes with signalling by proinflammatory
cytokines such as TNF 5 or IL-1 (e.g. a NIK, IKK, or MAP kinase
inhibitor); an IL-1 converting enzyme inhibitor; a TNF converting
enzyme inhibitor; a T-cell signalling inhibitor such as kinase
inhibitors; a metalloproteinase inhibitor; sulfasalazine;
azathioprine; a 6-mercaptopurine; an angiotensin converting enzyme
inhibitor; a soluble cytokine receptor (e.g. soluble p55 or p75 TNF
receptors, siL-lRI, siL-lRII, siL-6R), and an antiinflammatory
cytokine (e.g. IL-4, IL-10, IL-11, IL-13 or TGF).
For treating Crohn's disease, a compound of formula (I) or a
pharmaceutically acceptable salt thereof may be co-administered
with a TNF antagonist (e.g. an anti-TNF antibody), D2E7
(adalimumab), CA2 (infliximab), CDP 571, a TNFR-Ig construct,
(p75TNFRigG (etanercept)), a p55TNFRigG (LENERCEPT.TM.) inhibitor,
or a PDE4 inhibitor.
For treating inflammatory bowel disease, a compound of formula (I)
or a pharmaceutically acceptable salt thereof may be
co-administered with a corticosteroid (e.g. budenoside or
dexamethasone); sulfasalazine, 5-aminosalicylic acid; olsalazine;
an agent that interferes with synthesis or action of
proinflammatory cytokines such as IL-1 (e.g. an IL-1 converting
enzyme inhibitor or IL-1ra); a T cell signaling inhibitor (e.g. a
tyrosine kinase inhibitor); 6-mercaptopurine; IL-11; mesalamine;
prednisone; azathioprine; mercaptopurine; infliximab;
methylprednisolone sodium succinate; diphenoxylate/atrop sulfate;
loperamide hydrochloride; methotrexate; omeprazole; folate;
ciprofloxacin/dextrose-water; hydrocodone bitartrate/apap;
tetracycline hydrochloride; fluocinonide; metronidazole;
thimerosal/boric acid; cholestyramine/sucrose; ciprofloxacin
hydrochloride; hyoscyamine sulfate; meperidine hydrochloride;
midazolam hydrochloride; oxycodone HCl/acetaminophen; promethazine
hydrochloride; sodium phosphate; sulfamethoxazole/trimethoprim;
celecoxib; polycarbophil; propoxyphene napsylate; hydrocortisone;
multivitamins; balsalazide disodium; codeine phosphate/apap;
colesevelam HCl; cyanocobalamin; folic acid; levofloxacin;
methylprednisolone; natalizumab or interferon-gamma.
For treating multiple sclerosis, a compound of formula (I) or a
pharmaceutically acceptable salt thereof may be co-administered
with a corticosteroid; prednisolone; methylprednisolone;
azathioprine; cyclophosphamide; cyclosporine; methotrexate;
4-aminopyridine; tizanidine; interferon-1a (AVONEX.RTM.; Biogen);
interferon-1b (BETASERON.RTM.; Chiron/Berlex); interferon-n3)
(Interferon Sciences/Fujimoto), interferon--(Alfa
Wassermann/J&J), interferon 1A-IF (Serono/Inhale Therapeutics),
Peginterferon 2b (Enzon/Schering-Plough), Copolymer 1 (Cop-1;
COPAXONE.RTM.; Teva Pharmaceutical Industries, Inc.); hyperbaric
oxygen; intravenous immunoglobulin; cladribine; an antibody to or
antagonist of other human cytokines or growth factors and their
receptors (e.g. TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12,
IL-23, IL-15, IL-16, EMAP-1I, GM-CSF, FGF, or PDGF).
For treating AIDS a compound of formula (I) or a pharmaceutically
acceptable salt thereof may be co-administered with antibodies to
cell surface molecules such as CD2, CD3, CD4, CD8, CD19, CD20,
CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or their
ligands. A compound of Formula (I) or a pharmaceutically acceptable
salt thereof may also be co-administered with methotrexate,
cyclosporine, FK506, rapamycin, mycophenolate mofetil, leflunomide,
an S1P1 agonist, an NSAID (e.g. ibuprofen), a corticosteroid (e.g.
prednisolone), a phosphodiesterase inhibitor, an adensosine
agonist, an antithrombotic agent, acomplement inhibitor, a n
adrenergic agent, an agent that interferes with signalling by
proinflammatory cytokines such as TNF or IL-1 (e.g., a NIK, IKK,
p38 or MAP kinase inhibitor), an IL-1 converting enzyme inhibitor,
a TACE inhibitor, a T-cell signaling inhibitor (e. g. a kinase
inhibitor), a metalloproteinase inhibitor, sulfasalazine,
azathioprine, a 6-mercaptopurine, an angiotensin converting enzyme
inhibitor, a soluble cytokine receptor (e. g. soluble p55 or p75
TNF receptors, siL-lRI, siL-lRII, or siL-6R), or an
antiinflammatory cytokine (e.g. IL-4, IL-10, IL-13 or TGF).
A compound of formula (I) or a pharmaceutically acceptable salt
thereof may also be co-administered with agents, such as
alemtuzumab, dronabinol, daclizumab, mitoxantrone, xaliproden
hydrochloride, fampridine, glatiramer acetate, natalizumab,
sinnabidol, immunokine NNS03, ABR-215062, AnergiX.MS, chemokine
receptor antagonists, BBR-2778, calagualine, CPI-1189, LEM
(liposome encapsulated mitoxantrone), THC.CBD (cannabinoid
agonist), MBP-8298, mesopram (PDE4 inhibitor), MNA-715, a n
anti-IL-6 receptor antibody, neurovax, pirfenidone allotrap 1258
(RDP-1258), sTNF-R1, talampanel, teriflunomide, TGF-beta2,
tiplimotide, a VLA-4 antagonist (e.g. TR-14035, VLA4 Ultrahaler, or
Antegran-ELAN/Biogen), an interferon gamma antagonist, or an IL-4
agonist.
For treating ankylosing spondylitis a compound of formula (I) or a
pharmaceutically acceptable salt thereof may be co-administered
with ibuprofen, diclofenac, misoprostol, naproxen, meloxicam,
indomethacin, diclofenac, celecoxib, rofecoxib, sulfasalazine,
methotrexate, azathioprine, minocyclin, prednisone, a n anti-TNF
antibody, D2E7 (HUMIRA.RTM.), CA2 (infliximab), CDP 571, a TNFR-Ig
construct, (p75TNFRigG (ENBREL.RTM.), or p55TNFRigG
(LENERCEPT.RTM.).
For treating asthma a compound of formula (I) or a pharmaceutically
acceptable salt thereof may be co-administered with albuterol,
salmeterol/fluticasone, montelukast sodium, fluticasone propionate,
budesonide, prednisone, salmeterol xinafoate, levalbuterol HCl,
albuterol sulfate/ipratropium, prednisolone sodium phosphate,
triamcinolone acetonide, beclomethasone dipropionate, ipratropium
bromide, azithromycin, pirbuterol acetate, prednisolone,
theophylline anhydrous, methylprednisolone sodium succinate,
clarithromycin, zafirlukast, formoterol fumarate, influenza virus
vaccine, amoxicillin trihydrate, flunisolide, cromolyn sodium,
fexofenadine hydrochloride, flunisolide/menthol,
amoxicillin/clavulanate, levofloxacin, guaifenesin, dexamethasone
sodium phosphate, moxifloxacin HCl, doxycycline hyclate,
guaifenesin/d-methorphan, p-ephedrine/cod/chlorphenir,
gatifloxacin, cetirizine hydrochloride, mometasone furoate,
salmeterol xinafoate, benzonatate, cephalexin,
pe/hydrocodone/chlorphenir, cetirizine HCl/pseudoephed,
phenylephrine/cod/promethazine, codeine/promethazine, cefprozil,
dexamethasone, guaifenesin/pseudoephedrine,
chlorpheniramine/hydrocodone, nedocromil sodium, terbutaline
sulfate, epinephrine, methylprednisolone, an anti-IL-13 antibody,
or metaproterenol sulfate.
For treating COPD a compound of formula (I) or a pharmaceutically
acceptable salt thereof may be co-administered with albuterol
sulfate/ipratropium, ipratropium bromide, salmeterol/fluticasone,
albuterol, salmeterol xinafoate, fluticasone propionate,
prednisone, theophylline anhydrous, methylprednisolone sodium
succinate, montelukast sodium, budesonide, formoterol fumarate,
triamcinolone acetonide, levofloxacin, guaifenesin, azithromycin,
beclomethasone dipropionate, levalbuterol HCl, flunisolide,
ceftriaxone sodium, amoxicillin trihydrate, gatifloxacin,
zafirlukast, amoxicillin/clavulanate, flunisolide/menthol,
chlorpheniramine/hydrocodone, metaproterenol sulfate,
methylprednisolone, mometasone furoate,
p-ephedrine/cod/chlorphenir, pirbuterol acetate,
p-ephedrine/loratadine, terbutaline sulfate, tiotropium bromide,
(R,R)-formoterol, TgAAT, cilomilast, or roflumilast.
For treating psoriasis, a compound of formula (I) or a
pharmaceutically acceptable salt thereof may be co-administered
with calcipotriene, clobetasol propionate, triamcinolone acetonide,
halobetasol propionate, tazarotene, methotrexate, fluocinonide,
betamethasone diprop augmented, fluocinolone acetonide, acitretin,
tar shampoo, betamethasone valerate, mometasone furoate,
ketoconazole, pramoxine/fluocinolone, hydrocortisone valerate,
flurandrenolide, urea, betamethasone, clobetasol propionate/emoll,
fluticasone propionate, azithromycin, hydrocortisone, moisturizing
formula, folic acid, desonide, pimecrolimus, coal tar, diflorasone
diacetate, etanercept folate, lactic acid, methoxsalen, he/bismuth
subgal/znox/resor, methylprednisolone acetate, prednisone,
sunscreen, halcinonide, salicylic acid, anthralin, clocortolone
pivalate, coal extract, coal tar/salicylic acid, coal tar/salicylic
acid/sulfur, desoximetasone, diazepam, emollient,
fluocinonide/emollient, mineral oil/castor oil/na lact, mineral
oil/peanut oil, petroleum/isopropyl myristate, psoralen, salicylic
acid, soap/tribromsalan, thimerosal/boric acid, celecoxib,
infliximab, cyclosporine, alefacept, efalizumab, tacrolimus,
pimecrolimus, PUVA, UVB, sulfasalazine, ABT-874 or ustekinamab.
For treating psoriatic arthritis, a compound of formula (I) or a
pharmaceutically acceptable salt thereof may be co-administered
with methotrexate, etanercept, rofecoxib, celecoxib, folic acid,
sulfasalazine, naproxen, leflunomide, methylprednisolone acetate,
indomethacin, hydroxychloroquine sulfate, prednisone, sulindac,
betamethasone diprop augmented, infliximab, methotrexate, folate,
triamcinolone acetonide, diclofenac, dimethylsulfoxide, piroxicam,
diclofenac sodium, ketoprofen, meloxicam, methylprednisolone,
nabumetone, tolmetin sodium, calcipotriene, cyclosporine,
diclofenac sodium/misoprostol, fluocinonide, glucosamine sulfate,
gold sodium thiomalate, hydrocodone bitartrate/apap, ibuprofen,
risedronate sodium, sulfadiazine, thioguanine, valdecoxib,
alefacept, D2E7 (adalimumab), or efalizumab.
For treating lupus, a compound of formula (I) or a pharmaceutically
acceptable salt thereof may be co-administered with an NSAID (e.g.
diclofenac, naproxen, ibuprofen, piroxicam, or indomethacin); a
COX2 inhibitor (e.g. celecoxib, rofecoxib, or valdecoxib); an
anti-malarial (e.g. hydroxychloroquine); a steroid (e.g.
prednisone, prednisolone, budenoside, or dexamethasone); a
cytotoxic (e.g. azathioprine, cyclophosphamide, mycophenolate
mofetil, or methotrexate); a n inhibitor of PDE4, or a purine
synthesis inhibitor (e.g. Cellcept.RTM.). For example, a compound
of formula (I) or a pharmaceutically acceptable salt thereof may be
co-administered with sulfasalazine, 5-aminosalicylic acid,
olsalazine, Imuran.RTM., an agent that interferes with the
synthesis, production, or action of a proinflammatory cytokine
(e.g. IL-1), or a caspase inhibitor (e.g. a IL-1 converting enzyme
inhibitor or IL-1ra).
A compound of formula (I) or a pharmaceutically acceptable salt
thereof may also be co-administered with a T cell signaling
inhibitor (e.g. a tyrosine kinase inhibitor), or a molecule that
targets T cell activation (e.g. CTLA-4-IgG, an anti-B7 family
antibody, or an anti-PD-1 family antibody).
A compound of formula (I) or a pharmaceutically acceptable salt
thereof can also be co-administered with an IL-11 antibody, an
anti-cytokine antibody (e.g. fonotolizumab (anti-IFNg antibody)),
or an anti-receptor receptor antibodies (e.g. an anti-IL-6 receptor
antibody or an antibody to a B-cell surface molecule).
A compound of formula (I) or a pharmaceutically acceptable salt
thereof can also be co-administered with LJP 394 (abetimus), an
agent that depletes or inactivates B-cells (e.g. Rituximab
(anti-CD20 antibody) or lymphostat-B (anti-BlyS antibody)), a TNF
antagonist (e.g. an anti-TNF antibody), D2E7 (adalimumab), CA2
(infliximab), CDP 571, a TNFR-Ig construct, (p75TNFRigG
(etanercept), or p55TNFRigG (LENERCEPT.TM.).
A compound of formula (I) or a pharmaceutically acceptable salt
thereof can also be co-administered with one or more agents used in
the prevention or treatment of AIDS: an HIV reverse transcriptase
inhibitor, a n HIV protease inhibitor, an immunomodulator, or
another retroviral drug. Examples of reverse transcriptase
inhibitors include, but are not limited to, abacavir, adefovir,
didanosine, dipivoxil delavirdine, efavirenz, emtricitabine,
lamivudine, nevirapine, rilpivirine, stavudine, tenofovir,
zalcitabine, and zidovudine. Examples of protease inhibitors
include, but are not limited to, amprenavir, atazanavir, darunavir,
indinavir, fosamprenavir, lopinavir, nelfinavir, ritonavir,
saquinavir, and tipranavir. Examples of other retroviral drugs
include, but are not limited to, elvitegravir, enfuvirtide,
maraviroc and raltegravir.
For treating type II diabetes, hepatic steatosis, insulin
resistance, metabolic syndrome or a related disorder, a compound of
formula (I) or a pharmaceutically acceptable salt thereof may be
co-administered with insulin or insulins that have been modified to
improve the duration of action in the body; agents that stimulate
insulin secretion such as acetohexamide, chlorpropamide, glyburide,
glimepiride, glipizide, glicazide, glycopyramide, gliquidone,
rapaglinide, nataglinide, tolazamide or tolbutamide; agents that
are glucagon-like peptide agonists such as exanatide, liraglutide
or taspoglutide; agents that inhibit dipeptidyl-peptidase IV such
as vildagliptin, sitagliptin, saxagliptin, linagliptin, allogliptin
or septagliptin; agents that bind to the peroxisome
proliferator-activated receptor gamma such as rosiglitazone or
pioglitazone; agents that decrease insulin resistance such as
metformin; or agents that reduce glucose absorbance in the small
intestine such as acarbose, miglitol or voglibose.
For treating acute kidney disorders or a chronic kidney disease, a
compound of formula (I) or a pharmaceutically acceptable salt
thereof may be co-administered with dopamine, a diuretic (e.g.
furosemide), bumetanide, thiazide, mannitol, calcium gluconate,
sodium bicarbonate, albuterol, paricalcitol, doxercalciferol,
cinacalcet, or bardoxalone methyl.
The amount of both the compound of formula (I) or salt thereof and
additional agent (in those compositions which comprise an
additional therapeutic agent as described above) that may be
combined with the carrier materials to produce a single dosage form
will vary depending upon the host treated and the particular mode
of administration. In certain embodiments, compositions of this
invention are formulated such that a dosage of between 0.01-100
mg/kg body weight/day of an inventive can be administered.
The additional therapeutic agent and the compound of formula (I)
may act synergistically. Therefore, the amount of additional
therapeutic agent in such compositions may be less than that
required in a monotherapy utilizing only that therapeutic agent, or
there may be fewer side effects for the patient given that a lower
dose is used. In certain embodiments, in such compositions a dosage
of between 0.01-1,000 .mu.g/kg body weight/day of the additional
therapeutic agent can be administered.
Provided herein are methods of extending the duration of response
to a cytotoxic agent in an individual with cancer comprising
administering to the individual (a) an effective amount of a
compound of formula (I) or a pharmaceutically acceptable salt
thereof and (b) an effective amount of the cytotoxic agent.
In certain embodiments of any of the methods, the cytotoxic agent
is a targeted therapy. In certain embodiments, the targeted therapy
is one or more of an EGFR antagonist, RAF inhibitor, and/or PI3K
inhibitor.
In certain embodiments of any of the methods, the targeted therapy
is an EGFR antagonist. In certain embodiments of any of the
methods, the EGFR antagonist is
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine
and/or a pharmaceutical acceptable salt thereof. In certain
embodiments, the EGFR antagonist is
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine. In
certain embodiments, the EGFR antagonist is
N-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6-(5-((2-(methylsulfonyl)ethylam-
ino)methyl)furan-2-yl)quinazolin-4-amine,di4-methylbenzenesulfonate
or a pharmaceutically acceptable salt thereof (e.g.,
lapatinib).
In certain embodiments of any of the methods, targeted therapy is a
RAF inhibitor. In certain embodiments, the RAF inhibitor is a BRAF
inhibitor. In certain embodiments, the RAF inhibitor is a CRAF
inhibitor. In certain embodiments, the BRAF inhibitor is
vemurafenib. In certain embodiments, the RAF inhibitor is
3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(3-methyl-4-oxo-3,4-dihydroquinazoli-
n-6-ylamino)phenyl)benzamide or a pharmaceutically acceptable salt
thereof (e.g., AZ628 (CAS#878739-06-1)).
In certain embodiments of any of the methods, the targeted therapy
is a PI3K inhibitor.
In certain embodiments of any of the methods, the cytotoxic agent
is chemotherapy. In certain embodiments of any of the methods, the
chemotherapy is a taxane. In certain embodiments, the taxane is
paclitaxel. In certain embodiments, the taxane is docetaxel.
In certain embodiments of any of the methods, the cytotoxic agent
is a platinum agent. In certain embodiments, the platinum agent is
carboplatin. In certain embodiments, the platinum agent is
cisplatin. In certain embodiments of any of the methods, the
cytotoxic agent is a taxane and a platinum agent. In certain
embodiments, the taxane is paclitaxel. In certain embodiments, the
taxane is docetaxel. In certain embodiments, the platinum agent is
carboplatin. In certain embodiments, the platinum agent is
cisplatin.
In certain embodiments of any of the methods, the cytotoxic agent
is a vinca alkyloid. In certain embodiments, the vinca alkyloid is
vinorelbine. In certain embodiments of any of the methods, the
chemotherapy is a nucleoside analog. In certain embodiments, the
nucleoside analog is gemcitabine.
In certain embodiments of any of the methods, the cytotoxic agent
is radiotherapy.
In certain embodiments of any of the methods, the compound of
formula (I) or a pharmaceutically acceptable salt thereof is
concomitantly administered with the cytotoxic agent (e.g., targeted
therapy, chemotherapy, and/or radiotherapy). In certain
embodiments, the compound of formula (I) or a pharmaceutically
acceptable salt thereof is administered prior to and/or
concurrently with the cytotoxic agent (e.g., targeted therapy,
chemotherapy, and/or radiotherapy).
EXEMPLIFICATION
As depicted in the Examples below, in certain exemplary
embodiments, compounds are prepared according to the following
general procedures. It will be appreciated that, although the
general methods depict the synthesis of certain compounds of the
present invention, the following general methods, and other methods
known to one of ordinary skill in the art, can be applied to all
compounds and subclasses and species of each of these compounds, as
described herein.
##STR00137##
Representative compounds of formula (I) were prepared according to
the scheme shown above.
Intermediate A (prepared as described in the general synthesis of
intermediates) was treated with an alkylating agent and a base in a
solvent such as DMF or acetonitrile at elevated temperature to
provide the corresponding N--R.sup.1 substituted derivatives. Those
products were coupled with substituted aryl boronic acids under
Pd-catalyzed conditions to form biaryl intermediates from which the
tosyl group was removed under hydrolytic conditions to yield
compounds of formula (I).
##STR00138##
Representative compounds of formula (I) were prepared according to
the scheme shown above.
Intermediate A (prepared as described in the general synthesis of
intermediates) was treated with an alkylating agent and a base in a
solvent such as DMF or acetonitrile at elevated temperature to
provide the corresponding N--R.sup.1 substituted derivatives. Those
products were coupled with 3-borono-4-methoxybenzoic acid under
Pd-catalyzed conditions to form the corresponding biaryl
carboxylate. Those intermediates were coupled with various amines
to yield compounds of formula (I).
##STR00139##
Representative compounds of formula (I) were prepared according to
the scheme shown above.
Intermediate A (prepared as described in the general synthesis of
intermediates) was treated with an alkylating agent and a base in a
solvent such as DMF or acetonitrile at elevated temperature to
provide the corresponding N--R.sup.1 substituted derivatives. Those
products were coupled with (4-(methoxycarbonyl)phenyl)boronic acid
under Pd-catalyzed conditions to form the corresponding biaryl
esters. Addition of methylmagnesium bromide, followed by hydrolytic
removal of the tosyl group, yielded compounds of formula (I).
##STR00140##
Representative compounds of formula (I) were prepared according to
the scheme shown above.
Intermediate A (prepared as described in the general synthesis of
intermediates) was treated with an alkylating agent and a base in a
solvent such as DMF or acetonitrile at elevated temperature to
provide the corresponding N--R.sup.1 substituted bromides. Those
products were deprotected under hydrolytic conditions before being
coupled with
2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol
(prepared from 1,4-dibromobenze treated with butyl lithium and
quenched with acetone, followed by subsequent borylation) to form
compounds of formula (I)
##STR00141##
Representative compounds of formula (I) were prepared according to
the scheme shown above.
Intermediate B (prepared as described in the general synthesis of
intermediates) was treated with an alkylating agent and a base in a
solvent such as DMF or acetonitrile at elevated temperature to
provide the corresponding N--R.sup.1 substituted derivatives. Those
products were coupled (3-(dimethylcarbamoyl)phenyl)boronic acid
under Pd-catalyzed conditions to yield compounds of formula
(I).
General Procedure for the Preparation of Intermediate A
##STR00142## Step 1:
2-methoxy-4-methyl-3-nitropyridine
##STR00143##
A solution of 2-chloro-4-methyl-3-nitropyridine (250 g, 1.45 mol)
in methanol (1.0 L) was added dropwise (2 h) to a stirred and
cooled (0.degree. C.) solution of sodium methoxide (250 g, 4.63
mol) in methanol (850 mL). After addition, the mixture was heated
to reflux for 23 h, at which time TLC indicated the reaction had
gone to completion. The mixture was concentrated under reduced
pressure to a volume of approximately 900 mL, and quenched by
addition of water (1.5 L). The resulting solid was collected by
filtration, washed with water and dried under reduced pressure to
give the title compound (250 g, 100% yield) as a brown solid.
.sup.1H NMR (400 MHz, DMSO-d6): .delta. 8.22 (d, J=5.2 Hz, 1H),
7.10 (d, J=5.6 Hz, 1H), 3.92 (s, 3H), 2.26 (s, 3H).
Step 2:
5-bromo-2-methoxy-4-methyl-3-nitropyridine
##STR00144##
Sodium acetate (365 g, 5.37 mol) was added to a stirred solution of
2-methoxy-4-methyl-3-nitropyridine (250 g, 1.49 mol) in acetic acid
(1.5 L) at ambient temperature and then Br.sub.2 (639 g, 4.00 mol)
was added dropwise (30 min). After addition, the mixture was heated
at 80.degree. C. for 12 h, at which time TLC indicated the reaction
had gone to completion. The mixture was cooled (0.degree. C.) and
quenched by sequential addition of 10% aqueous (1.5 L) and
saturated aqueous sodium sulfate (1.5 L). The resulting solid was
collected by filtration, washed with water, and dried under reduced
pressure to give the title compound (302 g, 82.2% yield) as a light
yellow solid. .sup.1H NMR (400 MHz, DMSO-d6): .delta. 8.25 (s, 1H),
3.94 (s, 3H), 2.29 (s, 3H).
Step 3:
(E)-2-(5-bromo-2-methoxy-3-nitro-4-pyridyl)-N,N-dimethyl-ethenamine
##STR00145##
DMF-DMA (600 mL) was slowly added to a stirred and heated
(80.degree. C.) solution of
5-bromo-2-methoxy-4-methyl-3-nitropyridine (134 g, 0.54 mol) in DMF
(L1 L). After addition, the mixture was heated at 95.degree. C. for
5 h. The mixture was cooled to room temperature and poured into
ice-cold water (3 L). The resulting red solid was collected by
filtration, washed with water, and dried under reduced pressure to
give the title compound (167 g, 100% yield) as red solid. .sup.1H
NMR (400 MHz, DMSO-d6): .delta. 8.24 (s, 1H), 7.05 (d, J=13.6 Hz,
1H), 7.05 (d, J=13.6 Hz, 1H), 4.80 (d, J=13.2 Hz, 1H), 3.88 (s,
3H), 2.90 (s, 6H).
Step 4:
4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine
##STR00146##
A mixture of
2-(5-bromo-2-methoxy-3-nitropyridin-4-yl)-N,N-dimethylethenamine
(50.0 g, 165 mmol), Fe (50.0 g, 893 mmol) and NH.sub.4Cl (50.0 g,
943 mmol) in methanol/H.sub.2O (1900/250 mL) was heated at reflux
for 7 h, at which time LCMS indicated that the reaction had gone to
completion. The mixture was filtered while hot and the cake was
washed with methanol (3.times.200 mL). The combined filtrates were
concentrated under reduced pressure, and the resulting residue was
purified by silica gel chromatography (petroleum ether:ethyl
acetate=5:1) to yield the crude product. This crude material was
triturated with acetonitrile to give the title compound (37.4 g,
99.5% yield) as a light brown solid. LCMS M/Z (M+H) 226.7,
228.7.
Step 5:
4-bromo-7-methoxy-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine
##STR00147##
A solution of 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine (34.3 g,
0.15 mol) in THF (700 mL) was added dropwise to a stirred and
cooled (0.degree. C.) solution of sodium hydride (60%, 19.2 g, 0.48
mol) in THF (700 mL). After addition, the mixture was stirred at
room temperature for 1 h, and then cooled again to 0.degree. C.
Tosyl chloride (38.0 g, 0.20 mol) in THF (700 mL) was added
dropwise and the resulting mixture was stirred at ambient
temperature for 2 h. The reaction was quenched by addition of
saturated aqueous ammonium chloride (1.0 L), and then extracted
with ethyl acetate (3.times.600 mL). The combined organic extracts
were dried over sodium sulfate and concentrated under reduced
pressure. The residue was triturated with acetonitrile to give the
title compound (51.2 g, 88.9% yield) as a brown solid. This crude
material was used in the next step without further
purification.
Step 6:
4-bromo-1-(p-tolylsulfonyl)-6H-pyrrolo[2,3-c]pyridin-7-one
##STR00148##
HBr (40% aqueous, 1.1 L) was added to a solution of
4-bromo-7-methoxy-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine (102.5
g, 0.27 mol) in ethanol (200 mL). After addition, the mixture was
heated at 90.degree. C. for 2 h, at which time TLC indicated that
the reaction had gone to completion. The mixture was cooled to
0.degree. C. and the resulting white solid was collected by
filtration. This solid was washed with water and dried under vacuum
to give the title compound (Intermediate A) (87.5 g, 88.6% yield)
as a light brown solid. .sup.1H NMR (400 MHz, DMSO-d6): .delta.
11.48 (s, 1H), 8.01 (d, J=3.6 Hz, 1H), 8.90 (d, J=8.0 Hz, 2H), 7.38
(d, J=8.0 Hz, 2H), 7.32 (s, 1H), 6.57 (d, J=3.2 Hz, 1H), 2.34 (s,
3H).
General Procedure for the Preparation of Intermediate B
##STR00149## Step 1:
5-bromo-2-methoxy-3-nitropyridine
##STR00150##
Sodium methoxide (17.2 g, 318.4 mmol) was added to a stirred
solution of 5-bromo-2-chloro-3-nitropyridine (15.0 g, 64.2 mmol) in
methanol (125 mL). After addition, the reaction mixture was heated
at reflux for 2 h. The mixture was concentrated under reduced
pressure, and the residue was diluted with water (200 mL). The
resulting precipitate was collected by filtration, washed with
water, and dried under reduced pressure to give the title compound
(12.0 g, 81.5% yield) as a brown solid. .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 8.43 (d, J=2.4 Hz, 1H), 8.38 (d, J=2.0 Hz,
1H), 4.09 (s, 3H).
Step 2:
4-bromo-7-methoxy-2-methyl-1H-pyrrolo[2,3-c]pyridine
##STR00151##
Isopropenyl magnesium bromide (0.5 M in THF, 105.0 mL, 55.0 mmol)
was added dropwise to a stirred and cooled (-78.degree. C.)
solution of 5-bromo-2-methoxy-3-nitropyridine (4.0 g, 17.1 mmol) in
THF (40 mL). After addition, the resulting mixture was allowed to
warm to room temperature gradually and stirred for an additional 3
h. The reaction mixture was quenched by addition of 1 M aqueous
ammonium chloride (150 mL), and then extracted with ethyl acetate
(3.times.100 mL). The combined organic extracts were dried over
sodium sulfate and concentrated under reduced pressure. The residue
was purified by silica gel chromatography (petroleum ether:ethyl
acetate=10:1) to give the title compound (1.65 g, 39.9% yield) as
brown oil. LCMS M/Z (M+H) 240.1, 242.1.
Step 3:
4-bromo-2-methyl-1,6-dihydropyrrolo[2,3-c]pyridin-7-one
##STR00152##
Hydrogen bromide (40% aqueous, 20 mL) was added to a solution of
4-bromo-7-methoxy-2-methyl-1H-pyrrolo[2,3-c]pyridine (1.65 g, 6.8
mmol) in ethanol (10 mL). After addition, the reaction mixture was
heated at 90.degree. C. for 15 h, at which time TLC indicated the
reaction had gone to completion. The mixture was cooled to
0.degree. C. and the resulting solid was collected by filtration.
This solid was washed with water and dried to give title compound
(Intermediate B, 0.9 g, 57.9% yield) as a brown solid. .sup.1H NMR
(400 MHz, DMSO-d6): .delta. 12.06 (s, 1H), 11.00 (s, 1H), 7.03 (s,
1H), 5.97 (s, 1H), 2.29 (s, 3H). LCMS M/Z (M+H) 226.8, 228.8
Example 1
3-(6-allyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N,N-dimethyl-benzamide
##STR00153## Step 1
6-allyl-4-bromo-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridin-7-one
##STR00154##
To a cooled (0.degree. C.) solution of
4-bromo-1-(p-tolylsulfonyl)-6H-pyrrolo[2,3-c]pyridin-7-one
(intermediate A) (300 mg, 0.8 mmol) in DMF (4 mL) was added sodium
hydride (60% in mineral oil, 50 mg, 1.0 mmol) The mixture was
stirred for 15 min and then 3-bromoprop-1-ene (100 mg, 1.0 mmol)
was added. The reaction mixture was allowed to warm to room
temperature and stirring was continued for 2 h. The reaction was
quenched with water (20 mL) and then extracted with ethyl acetate
(3.times.20 mL). The combined organic extracts were washed with
brine (2.times.20 mL), dried over sodium sulfate and concentrated
under reduced pressure to yield the title compound (350 mg, 100%
yield) as a yellow solid. This crude material was used in the next
step without further purification. LCMS M/Z (M+H) 409.3.
Step 2
3-[6-allyl-7-oxo-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridin-4-yl]-N,N-dimeth-
yl-benzamide
##STR00155##
To a mixture of
3-[6-allyl-7-oxo-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridin-4-yl]-N,N-dimet-
hyl-benzamide (Step 1, 350 mg, 0.86 mmol) and
[3-(dimethylcarbamoyl)phenyl]boronic acid (220 mg, 1.1 mmol) in
acetonitrile (2 mL) and 1 M potassium carbonate in water (2 mL) was
added [1,1'-bis(diphenylphosphino)ferrocene]palladium(ii)
dichloride (63 mg, 0.086 mmol). The reaction mixture was subjected
to microwave irradiation at 100.degree. C. for 10 minutes. The
mixture was filtered through a pad of Celite, using ethyl acetate
(30 mL) to rinse. The filtrate was washed with brine (10 mL), dried
over sodium sulfate and concentrated under reduced pressure to
yield the title compound (300 mg, 70% yield) as a yellow solid.
This crude material was used in the next step without further
purification. LCMS M/Z (M+H) 476.4.
Step 3
3-(6-allyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N,N-dimethyl-benzamide
##STR00156##
A mixture of
3-[6-allyl-7-oxo-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridin-4-yl]-N,N-dimet-
hyl-benzamide (Step 2, 35 mg, 0.074 mmol) in methanol (1 mL) and 10
M potassium hydroxide in water (0.8 mL) was stirred at 50.degree.
C. for 1 h. After cooling, the reaction mixture was concentrated
under reduced pressure. The residue was dissolved in water (5 mL)
and extracted with ethyl acetate (3.times.10 mL). The combined
organic extracts were dried over sodium sulfate, filtered and
concentrated under reduced pressure. The residue was purified by
preparative HPLC (25-35% ACN/0.1% NH4OH in H2O) to give the title
compound (13 mg, 65% yield) as a white solid. .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 7.66 (m, J=7.7, 1.4 Hz, 1H), 7.58-7.49 (m, 211),
7.41-7.31 (m, 3H), 6.44 (d, J=2.7 Hz, 1H), 6.02 (in, J=17.2, 10.7,
5.5 Hz, 111), 5.21-5.08 (m, 2H), 4.68 (m, J=5.5, 1.6 Hz, 2H), 2.99
(m, J=11.6 Hz, 6H). LCMS M/Z (M+H) 322.2.
The following compounds were prepared in a similar fashion to
Example 1:
Examples 2-54
TABLE-US-00002 Example IUPAC Name NMR m/z 2 3-(6-butyl-7-oxo-1H-
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 12.11 (s, 1H), 338.2
pyrrolo[2,3- 7.67 (dt, J = 7.8, 1.4 Hz, 1H), 7.57 (t, J = 1.7 Hz,
c]pyridin-4-yl)-N,N- 1H), 7.52 (t, J = 7.7 Hz, 1H), 7.41 (s, 1H),
7.35 (dt, dimethyl-benzamide J = 7.7, 1.6 Hz, 2H), 6.43 (d, J = 2.8
Hz, 1H), 4.04 (t, J = 7.3 Hz, 2H), 2.99 (m, J = 11.1 Hz, 6H),
1.83-1.62 (m, 2H), 1.33 (h, J = 7.4 Hz, 2H), 0.92 (t, J = 7.4 Hz,
3H). 3 N,N-dimethyl-3-[6- .sup.1H NMR (400 MHz, DMSO-d6) .delta.
12.13 (s, 1H), 350.2 (3-methylbut-2-enyl)- 7.65 (dt, J = 7.8, 1.5
Hz, 1H), 7.56 (t, J = 1.7 Hz, 7-oxo-1H- 1H), 7.52 (t, J = 7.7 Hz,
1H), 7.39-7.36 (m, 2H), pyrrolo[2,3- 7.34 (d, J = 4.9 Hz, 1H), 6.42
(dd, J = 2.9, 1.6 Hz, c]pyridin-4- 1H), 5.46-5.25 (m, 1H), 4.65 (d,
J = 6.9 Hz, 2H), yl]benzamide 2.99 (m, J = 10.6 Hz, 6H), 1.80 (d, J
= 1.3 Hz, 3H), 1.70 (d, J = 1.3 Hz, 3H). 4 3-[6-(2- .sup.1H NMR
(400 MHz, DMSO-d6) .delta. 12.12 (s, 1H), 350.2
cyclopropylethyl)-7- 7.48 (dd, J = 7.5, 1.9 Hz, 1H), 7.41 (dd, J =
7.7, 1.6 Hz, oxo-1H-pyrrolo[2,3- 1H), 7.37 (s, 1H), 7.35-7.24 (m,
3H), 6.19 (d, c]pyridin-4-yl]-N,N- J = 2.8 Hz, 1H), 3.53 (m, J =
3.8 Hz, 6H), 2.88 (d, J = 11.2 Hz, dimethyl-benzamide 2H), 2.83 (s,
3H), 2.24 (s, 1H), 2.06 (d, J = 8.3 Hz, 2H), 1.89-1.74 (m, 2H),
1.62 (d, J = 11.7 Hz, 2H). 5 3-[6- .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 12.11 (s, 1H), 364.2 (cyclopentylmethyl)- 7.67 (dt, J =
7.8, 1.4 Hz, 1H), 7.57 (t, J = 1.7 Hz, 7-oxo-1H- 1H), 7.52 (t, J =
7.7 Hz, 1H), 7.41 (s, 1H), pyrrolo[2,3- 7.39-7.32 (m, 2H), 6.43
(dd, J = 2.9, 1.6 Hz, 1H), 4.00 (d, c]pyridin-4-yl]-N,N- J = 7.6
Hz, 2H), 3.06-2.93 (m, 6H), dimethyl-benzamide 2.46-2.35 (m, 1H),
1.62 (m, J = 15.2, 10.9, 9.9, 5.5 Hz, 4H), 1.51 (m, J = 9.6, 5.1
Hz, 2H), 1.39-1.25 (m, 2H). 6 3-[6-[(4- .sup.1H NMR (400 MHz,
DMSO-d6 .delta. 12.17 (s, 1H), 402.2 methoxyphenyl)methyl]- 7.63
(dt, J = 7.9, 1.4 Hz, 1H), 7.56-7.47 (m, 3H), 7-oxo-1H- 7.41-7.30
(m, 4H), 6.91-6.85 (m, 2H), 6.43 (d, J = 2.8 Hz, pyrrolo[2,3- 1H),
5.20 (s, 2H), 3.70 (s, 2H), 2.98 (m, J = 14.1 Hz,
c]pyridin-4-yl]-N,N- 6H). dimethyl-benzamide 7 N,N-dimethyl-3-[7-
.sup.1H NMR (400 MHz, DMSO-d6 .delta. 12.17 (s, 1H), 350.2
oxo-6-[(E)-pent-2- 7.66 (dt, J = 7.8, 1.5 Hz, 1H), 7.60-7.46 (m,
2H), enyl]-1H-pyrrolo[2,3- 7.41-7.30 (m, 3H), 6.43 (q, J = 2.4 Hz,
1H), c]pyridin-4- 5.83-5.51 (m, 2H), 4.75-4.56 (m, 2H), 2.99 (d, J
= 13.5 Hz, yl]benzamide 6H), 2.01 (ddd, J = 7.6, 6.1, 1.4 Hz, 2H),
0.96 (dt, J = 23.0, 7.4 Hz, 3H). 8 3-(6-but-3-enyl-7- .sup.1H NMR
(400 MHz, DMSO-d6) .delta. 12.14 (s, 1H), 336.1 oxo-1H-pyrrolo[2,3-
7.67 (dt, J = 7.8, 1.4 Hz, 1H), 7.57 (t, J = 1.7 Hz,
c]pyridin-4-yl)-N,N- 1H), 7.52 (t, J = 7.7 Hz, 1H), 7.42 (s, 1H),
dimethyl-benzamide 7.38-7.32 (m, 2H), 6.43 (d, J = 2.8 Hz, 1H),
5.99-5.75 (m, 1H), 5.17-4.94 (m, 2H), 4.12 (m, J = 7.3 Hz, 2H),
2.99 (d, J = 13.3 Hz, 6H). 9 3-[6- .sup.1H NMR (400 MHz, DMSO-d6))
.delta. 12.12 (s, 1H), 378.2 (cyclohexylmethyl)- 7.72-7.60 (m, 1H),
7.58-7.46 (m, 2H), 7-oxo-1H- 7.40-7.28 (m, 3H), 6.43 (t, J = 2.2
Hz, 1H), 3.90 (d, J = 7.3 Hz, pyrrolo[2,3- 2H), 2.99 (d, J = 13.0
Hz, 6H), 1.84 (t, J = 3.5 Hz, c]pyridin-4-yl]-N,N- 1H), 1.76-1.48
(m, 5H), 1.27-0.93 (m, dimethyl-benzamide 5H). 10
3-(6-isopentyl-7-oxo- .sup.1H NMR (400 MHz, DMSO-d6)) .delta. 7.67
(dd, J = 8.1, 352.2 1H-pyrrolo[2,3- 1.7 Hz, 1H), 7.57 (d, J = 1.8
Hz, 1H), c]pyridin-4-yl)-N,N- 7.56-7.45 (m, 1H), 7.42 (s, 1H),
7.38-7.32 (m, 2H), dimethyl-benzamide 6.43 (t, J = 2.3 Hz, 1H),
4.03 (t, J = 7.4 Hz, 2H), 2.99 (d, J = 13.2 Hz, 6H), 1.70 (q, J =
7.2 Hz, 2H), 1.32 (q, J = 9.3, 8.1 Hz, 4H), 0.87 (t, J = 6.9 Hz,
3H). 11 3-[6- .sup.1H NMR (400 MHz, DMSO-d6) .delta. 12.15 (s, 1H),
350.2 (cyclobutylmethyl)-7- 7.66 (dt, J = 7.8, 1.4 Hz, 1H),
7.58-7.49 (m, 2H), oxo-1H-pyrrolo[2,3- 7.41 (s, 1H), 7.38-7.32 (m,
2H), 6.43 (d, J = 2.8 Hz, c]pyridin-4-yl]-N,N- 1H), 4.09 (d, J =
7.3 Hz, 2H), 2.99 (d, J = 13.3 Hz, dimethyl-benzamide 6H), 2.78 (p,
J = 7.3 Hz, 1H), 1.94 (s, 6H). 12 3-[6-(2- .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 12.12 (s, 1H), 392.2 cyclohexylethyl)-7- 7.67 (d,
J = 7.8 Hz, 1H), 7.53 (dd, J = 17.7, 10.1 Hz, oxo-1H-pyrrolo[2,3-
3H), 7.43-7.32 (m, 3H), 6.42 (d, J = 2.5 Hz, c]pyridin-4-yl]-N,N-
1H), 4.07 (m, J = 13.4, 5.5 Hz, 2H), 3.10-2.79 (m,
dimethyl-benzamide 6H), 1.78 (d, J = 12.8 Hz, 4H), 1.67 (m, 3H),
1.29 (m, 3H), 0.95 (m, J = 11.7 Hz, 4H). 13 N,N-dimethyl-3-(7-
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 12.12 (s, 1H), 352.2
oxo-6-pentyl-1H- 7.70-7.66 (m, 1H), 7.58 (t, J = 1.7 Hz, 1H), 7.52
(t, pyrrolo[2,3- J = 7.7 Hz, 1H), 7.41 (s, 1H), 7.38-7.34 (m, 2H),
c]pyridin-4- 6.43 (d, J = 2.8 Hz, 1H), 4.06 (m, J = 7.0 Hz, 2H),
yl)benzamide 2.99 (m, J = 13.6 Hz, 6H), 1.71-1.50 (m, 3H), 0.94 (m,
J = 6.1 Hz, 5H). 14 3-[6-(2- .sup.1H NMR (400 MHz, DMSO-d6))
.delta. 12.17 (s, 1H), 340.2 methoxyethyl)-7-oxo- 7.66 (m, J = 7.8,
1.5 Hz, 1H), 7.60-7.49 (m, 2H), 1H-pyrrolo[2,3- 7.43-7.31 (m, 3H),
6.44 (d, J = 2.8 Hz, 1H), c]pyridin-4-yl]-N,N- 4.22 (m, J = 5.6 Hz,
2H), 3.64 (m, J = 5.5 Hz, 2H), dimethyl-benzamide 3.26 (s, 3H),
2.99 (d, J = 13.1 Hz, 6H). 15 3-[6-(3- .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 12.16 (s, 1H), 354.2 methoxypropyl)-7- 7.68 (dt, J
= 7.7, 1.5 Hz, 1H), 7.60-7.47 (m, 2H), oxo-1H-pyrrolo[2,3-
7.41-7.30 (m, 3H), 6.43 (d, J = 2.8 Hz, 1H), c]pyridin-4-yl]-N,N-
4.09 (t, J = 7.2 Hz, 2H), 3.38 (t, J = 6.2 Hz, 2H), 3.24 (d,
dimethyl-benzamide J = 1.2 Hz, 3H), 3.09-2.87 (m, 6H), 1.95 (t, J =
7.0 Hz, 2H). 16 3-(6-isobutyl-7-oxo- .sup.1H NMR (400 MHz,
DMSO-d6)) .delta. 12.14 (s, 1H), 338 1H-pyrrolo[2,3- 7.69-7.65 (m,
1H), 7.56 (t, J = 1.8 Hz, 1H), c]pyridin-4-yl)-N,N- 7.53 (d, J =
7.7 Hz, 1H), 7.37 (d, J = 5.7 Hz, 2H), dimethyl-benzamide 6.44 (d,
J-2.7 Hz, 1H), 3.88 (d, J = 7.4 Hz, 2H), 3.07-2.92 (m, 6H),
2.33-1.79 (m, 1H), 0.90 (m, J = 6.7 Hz, 6H). 17 3-[6- .sup.1H NMR
(400 MHz, DMSO-d6) .delta. 12.16 (s, 1H), 336.2
(cyclopropylmethyl)- 7.68 (m, J = 7.8, 1.4 Hz, 1H), 7.58 (t, J =
1.8 Hz, 7-oxo-1H- 1H), 7.53 (t, J = 7.7 Hz, 1H), 7.47 (s, 1H),
pyrrolo[2,3- 7.40-7.33 (m, 2H), 6.44 (m, J = 2.8, 1.4 Hz, 1H), 3.92
(d, c]pyridin-4-yl]-N,N- J = 7.1 Hz, 2H), 3.09-2.92 (m, 6H), 1.30
(m, J = 12.6, dimethyl-benzamide 7.6, 5.1 Hz, 1H), 0.57-0.36 (m,
4H). 18 6-but-3-enyl-4-[3-(5- .sup.1H NMR (400 MHz, DMSO-d6))
.delta. 12.17 (s, 1H), 347.2 methyl-1,3,4- 8.17 (t, J = 1.8 Hz,
1H), 7.93 (m, J = 7.7, 1.4 Hz, oxadiazol-2- 1H), 7.84 (m, J = 7.9,
1.4 Hz, 1H), 7.68 (t, J = 7.8 Hz, yl)phenyl]-1H- 1H), 7.51 (s, 1H),
7.39 (d, J = 2.8 Hz, 1H), pyrrolo[2,3- 6.47 (d, J = 2.8 Hz, 1H),
5.96-5.79 (m, 1H), c]pyridin-7-one 5.13-4.98 (m, 2H), 4.14 (m, J =
7.2 Hz, 2H), 2.61 (s, 3H). 19 3-[6-[(E)-but-2-enyl]- 1H NMR (400
MHz, DMSO-d6) .delta. 12.19 (s, 1H), 354 7-oxo-1H- 7.50-7.35 (m,
4H), 7.22 (ddd, J = 8.9, 2.5, 1.3 Hz, pyrrolo[2,3- 1H), 6.45 (d, J
= 2.7 Hz, 1H), 5.76-5.56 (m, 2H), c]pyridin-4-yl]-5- 4.60 (d, J =
4.8 Hz, 2H), 2.98 (d, J = 15.3 Hz, 6H), fluoro-N,N-dimethyl- 1.65
(d, J = 4.1 Hz, 3H). benzamide 20 4-[6-[(E)-but-2-enyl]- 1H NMR
(400 MHz, DMSO) .delta. 12.18 (s, 1H), 326 7-oxo-1H- 7.77 (t, J =
8.0 Hz, 1H), 7.63 (d, J = 13.9 Hz, 2H), pyrrolo[2,3- 7.53-7.49 (m,
1H), 7.49-7.43 (m, 2H), 7.39 (d, J = 2.8 Hz, c]pyridin-4-yl]-2-
1H), 6.50 (d, J = 2.8 Hz, 1H), 5.74-5.57 (m, fluoro-benzamide 2H),
4.64-4.56 (m, 2H), 1.69-1.60 (m, 3H). 21 6-but-2-enyl-4-[4-(4-
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 12.14 (s, 1H), 392
methylpiperazine-1- 7.69-7.62 (m, 2H), 7.51-7.44 (m, 2H),
carbonyl)phenyl]-1H- 7.40-7.32 (m, 2H), 6.48 (d, J = 2.8 Hz, 1H),
pyrrolo[2,3- 5.75-5.60 (m, 2H), 4.65-4.57 (m, 2H), 3.30 (s, 3H),
c]pyridin-7-one 2.43-2.24 (m, 5H), 2.21 (s, 3H), 1.67-1.61 (m, 3H).
22 3-(6-but-2-enyl-7- .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
12.18 (s, 1H), 326 oxo-1H-pyrrolo[2,3- 8.10 (s, 1H), 7.93 (t, J =
1.5 Hz, 1H), c]pyridin-4-yl)-5- 7.65-7.57 (m, 1H), 7.57-7.51 (m,
2H), 7.44 (s, 1H), 7.39 (t, J = 2.7 Hz, fluoro-benzamide 1H),
6.50-6.44 (m, 1H), 5.71-5.60 (m, 2H), 4.60 (d, J = 4.5 Hz, 2H),
1.69-1.62 (m, 3H). 23 6-but-2-enyl-4-(4- .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 12.08 (s, 1H), 321 tert-butylphenyl)-1H-
7.54-7.44 (m, 4H), 7.34 (t, J = 2.8 Hz, 1H), pyrrolo[2,3- 7.21 (s,
1H), 6.47-6.42 (m, 1H), 5.74-5.59 (m, 2H), c]pyridin-7-one
4.64-4.55 (m, 2H), 1.68-1.62 (m, 3H), 1.32 (s, 9H). 24
4-(6-but-2-enyl-7- .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
12.15 (s, 1H), 322 oxo-1H-pyrrolo[2,3- 8.44 (q, J = 4.5 Hz, 1H),
7.98-7.89 (m, 2H), c]pyridin-4-yl)-N- 7.70-7.62 (m, 2H), 7.41-7.34
(m, 2H), 6.51-6.44 (m, methyl-benzamide 1H), 5.72-5.60 (m, 2H),
4.61 (d, J = 4.3 Hz, 2H), 2.81 (d, J = 4.5 Hz, 3H), 1.65 (d, J =
4.2 Hz, 3H). 25 3-(6-but-2-enyl-7- .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 12.14 (s, 1H), 322 oxo-1H-pyrrolo[2,3- 8.46
(d, J = 4.8 Hz, 1H), 8.01-7.99 (m, 1H), c]pyridin-4-yl)-N-
7.80-7.75 (m, 1H), 7.73-7.68 (m, 1H), 7.58-7.51 (m,
methyl-benzamide 1H), 7.37 (t, J = 2.8 Hz, 1H), 7.33 (s, 1H),
6.48-6.42 (m, 1H), 5.70-5.63 (m, 2H), 4.65-4.57 (m, 2H), 2.81 (d, J
= 4.5 Hz, 3H), 1.69-1.61 (m, 3H). 26 3-(6-but-2-enyl-7- .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 12.14 (s, 1H), 348
oxo-1H-pyrrolo[2,3- 8.46 (d, J = 4.2 Hz, 1H), 7.97 (t, J = 1.7 Hz,
1H), c]pyridin-4-yl)-N- 7.79-7.73 (m, 1H), 7.73-7.68 (m, 1H), 7.53
(t, J = 7.7 Hz, cyclopropyl- 1H), 7.37 (t, J = 2.8 Hz, 1H), 7.32
(s, 1H), benzamide 6.46-6.41 (m, 1H), 5.73-5.57 (m, 2H), 4.61 (d, J
= 4.1 Hz, 2H), 2.93-2.80 (m, 1H), 1.69-1.62 (m, 3H), 0.76-0.65 (m,
2H), 0.62-0.52 (m, 2H). 27 6-but-2-enyl-4-[3- .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 12.14 (s, 1H), 362 (pyrrolidine-1- 7.70-7.63
(m, 2H), 7.56-7.49 (m, 1H), carbonyl)phenyl]-1H- 7.49-7.43 (m, 1H),
7.37 (t, J = 2.8 Hz, 1H), 7.34 (d, J = 4.0 Hz, pyrrolo[2,3- 1H),
6.46-6.40 (m, 1H), 5.71-5.62 (m, c]pyridin-7-one 2H), 4.60 (d, J =
4.2 Hz, 2H), 3.49 (t, J = 6.8 Hz, 2H), 3.43 (t, J = 6.4 Hz, 2H),
1.94-1.75 (m, 5H), 1.69-1.61 (m, 2H). 28 4-(6-but-2-enyl-7- .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 12.15 (s, 1H), 348
oxo-1H-pyrrolo[2,3- 8.43 (d, J = 4.2 Hz, 1H), 7.94-7.87 (m, 2H),
c]pyridin-4-yl)-N- 7.68-7.62 (m, 2H), 7.40-7.36 (m, 2H), 6.49-6.44
(m, cyclopropyl- 1H), 5.69-5.64 (m, 2H), 4.63-4.58 (m, 2H),
benzamide 2.93-2.80 (m, 1H), 1.68-1.62 (m, 3H), 0.75-0.65 (m, 2H),
0.64-0.53 (m, 2H). 29 6-but-2-enyl-4-[4- .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 12.09 (s, 1H), 295 (hydroxymethyl)phenyl]-
7.57-7.48 (m, 2H), 7.42-7.37 (m, 2H), 7.35 (t, J = 2.8 Hz,
1H-pyrrolo[2,3- 1H), 7.24 (s, 1H), 6.46-6.39 (m, 1H),
c]pyridin-7-one 5.72-5.61 (m, 2H), 5.18 (t, J = 5.7 Hz, 1H),
4.64-4.57 (m, 2H), 4.54 (d, J = 5.7 Hz, 2H), 1.70-1.59 (m, 3H). 30
3-(6-but-2-enyl-7- .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
12.14 (s, 1H), 308 oxo-1H-pyrrolo[2,3- 8.11-7.98 (m, 2H), 7.84-7.80
(m, 1H), c]pyridin-4- 7.76-7.69 (m, 1H), 7.53 (t, J = 7.7 Hz, 1H),
7.38 (q, J = 3.3, yl)benzamide 2.8 Hz, 2H), 7.34 (s, 1H), 6.50-6.41
(m, 1H), 5.66 (t, J = 4.1 Hz, 2H), 4.61 (d, J = 4.0 Hz, 2H),
1.70-1.61 (m, 3H). 31 6-but-2-enyl-4-(4- .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 12.08 (s, 1H), 307 isopropylphenyl)-1H-
7.54-7.46 (m, 2H), 7.38-7.28 (m, 3H), 7.21 (s, pyrrolo[2,3- 1H),
6.48-6.39 (m, 1H), 5.76-5.57 (m, 2H), c]pyridin-7-one 4.59 (d, J =
5.4 Hz, 2H), 3.00-2.87 (m, 1H), 1.69-1.62 (m, 3H), 1.24 (d, J = 6.9
Hz, 6H). 32 3-(6-but-2-enyl-7- .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 12.14 (s, 1H), 336 oxo-1H-pyrrolo[2,3- 7.70-7.63 (m, 1H),
7.58-7.46 (m, 2H), c]pyridin-4-yl)-N,N- 7.40-7.31 (m, 3H),
6.45-6.39 (m, 1H), 5.67 (d, J = 4.8 Hz, dimethyl-benzamide 1H),
4.64-4.56 (m, 2H), 2.99 (d, J = 10.1 Hz, 7H), 1.68-1.61 (m, 3H). 33
6-but-2-enyl-4-[4- .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
12.14 (s, 1H), 362 (pyrrolidine-1- 7.62 (d, J = 4.9 Hz, 3H),
7.49-7.27 (m, 2H), carbonyl)phenyl]-1H- 6.57-6.37 (m, 1H),
5.74-5.61 (m, 1H), 4.61 (d, J = 5.1 Hz, pyrrolo[2,3- 2H), 3.53-3.41
(m, 5H), 1.95-1.73 (m, 5H), c]pyridin-7-one 1.73-1.46 (m, 3H). 34
N-[4-(6-but-2-enyl-7- .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
12.09 (s, 1H), 358 oxo-1H-pyrrolo[2,3- 9.77 (s, 1H), 7.58-7.51 (m,
2H), 7.35 (t, J = 2.8 Hz, c]pyridin-4- 1H), 7.33-7.27 (m, 2H), 7.22
(s, 1H), yl)phenyl]methanesulfonamide 6.47-6.42 (m, 1H), 5.69-5.63
(m, 2H), 4.58 (d, J = 4.7 Hz, 2H), 3.01 (s, 3H), 1.70-1.61 (m, 3H).
35 3-(6-but-2-enyl-7- .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
12.14 (s, 1H), 350 oxo-1H-pyrrolo[2,3- 8.25 (d, J = 7.7 Hz, 1H),
7.99 (t, J = 1.8 Hz, 1H), c]pyridin-4-yl)-N- 7.82-7.77 (m, 1H),
7.73-7.67 (m, 1H),
isopropyl-benzamide 7.62-7.50 (m, 1H), 7.37 (t, J = 2.7 Hz, 1H),
7.32 (s, 1H), 6.47-6.37 (m, 1H), 5.67 (d, J = 4.5 Hz, 1H), 4.61 (d,
J = 4.1 Hz, 2H), 4.21-4.03 (m, 1H), 1.68-1.61 (m, 2H), 1.24-1.15
(m, 8H). 36 4-(6-but-2-enyl-7- .sup.1N NMR (400 MHz, DMSO-d.sub.6)
.delta. 12.14 (s, 1H), 336 oxo-1H-pyrrolo[2,3- 7.68-7.61 (m, 1H),
7.53-7.47 (m, 2H), c]pyridin-4-yl)-N,N- 7.38-7.35 (m, 1H), 7.35 (s,
1H), 6.62-6.32 (m, 1H), dimethyl-benzamide 5.83-5.58 (m, 2H),
4.68-4.44 (m, 2H), 2.99 (s, 7H), 1.68-1.63 (m, 3H). 37
6-but-2-enyl-4-[4- .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
12.15 (s, 1H), 378 (morpholine-4- 7.70-7.61 (m, 2H), 7.52-7.48 (m,
2H), carbonyl)phenyl]-1H- 7.41-7.33 (m, 2H), 6.50-6.44 (m, 1H),
5.74-5.60 (m, pyrrolo[2,3- 1H), 4.60 (d, J = 5.1 Hz, 2H), 3.62 (s,
5H), 3.29 (d, c]pyridin-7-one J = 1.5 Hz, 4H), 1.69-1.63 (m, 3H).
38 3-(6-but-2-enyl-7- 1H NMR (400 MHz, DMSO-d6) d 12.02 (br. s.,
319 oxo-1H-pyrrolo[2,3- 2H), 7.86 (dd, J = 2.18, 8.62 Hz, 1H),
c]pyridin-4-yl)-4- 7.70-7.75 (m, 1H), 7.51-7.67 (m, 1H), 7.25-7.33
(m, 3H), methoxy-benzonitrile 7.16-7.24 (m, 1H), 6.04 (t, J = 2.29
Hz, 1H), 5.50-5.75 (m, 3H), 4.67 (d, J = 6.86 Hz, 1H), 4.56 (d, J =
4.57 Hz, 2H), 3.82 (s, 4H), 1.77 (dd, J = 1.35, 6.75 Hz, 1H), 1.65
(d, J = 4.99 Hz, 3H) 39 3-[6-[(E)-but-2-enyl]- 326 7-oxo-1H-
pyrrolo[2,3- c]pyridin-4-yl]-2- fluoro-benzamide 40
3-[6-[(E)-but-2-enyl]- 1H NMR (400 MHz, DMSO) .delta. 12.12 (s,
1H), 326 7-oxo-1H- 8.08-7.98 (m, 2H), 7.98-7.88 (m, 1H), 7.45-7.37
(m, pyrrolo[2,3- 2H), 7.37-7.25 (m, 2H), 6.20-6.13 (m, 1H),
c]pyridin-4-yl]-4- 5.78-5.56 (m, 2H), 4.60 (d, J = 3.8 Hz, 2H),
1.66 (d, J = 4.9 Hz, fluoro-benzamide 3H). 41
3-[6-[(E)-but-2-enyl]- 1H NMR (400 MHz, DMSO) .delta. 7.54-7.51 (m,
1H), 354 7-oxo-1H- 7.49-7.44 (m, 1H), 7.41-7.35 (m, 1H),
pyrrolo[2,3- 7.34-7.32 (m, 1H), 7.29 (d, J = 0.5 Hz, 1H),
c]pyridin-4-yl]-4- 6.23-6.12 (m, 1H), 5.77-5.56 (m, 2H), 4.67-4.51
(m, 2H), fluoro-N,N-dimethyl- 2.98 (s, 6H), 1.65 (d, J = 4.8 Hz,
3H). benzamide 42 3-[6-[(E)-but-2-enyl]- 354 7-oxo-1H- pyrrolo[2,3-
c]pyridin-4-yl]-2- fluoro-N,N-dimethyl- benzamide 43
4-[6-[(E)-but-2-enyl]- 1H NMR (400 MHz, DMSO) .delta. 7.54-7.51 (m,
1H), 370 7-oxo-1H- 7.49-7.44 (m, 1H), 7.41-7.35 (m, 1H),
pyrrolo[2,3- 7.34-7.32 (m, 1H), 7.29 (d, J = 0.5 Hz, 1H),
c]pyridin-4-yl]-2- 6.23-6.12 (m, 1H), 5.77-5.56 (m, 2H), 4.67-4.51
(m, 2H), chloro-N,N-dimethyl- 2.98 (s, 6H), 1.65 (d, J = 4.8 Hz,
3H). benzamide 44 4-[6-[(E)-but-2-enyl]- 1H NMR (400 MHz, DMSO)
.delta. 12.12 (s, 1H), 342 7-oxo-1H- 7.56-7.50 (m, 1H), 7.50-7.44
(m, 1H), 7.43-7.35 (m, pyrrolo[2,3- 1H), 7.34-7.32 (m, 1H),
7.30-7.27 (m, 1H), c]pyridin-4-yl]-2- 6.17 (t, J = 2.6 Hz, 1H),
5.76-5.59 (m, 2H), 4.59 (d, J = 4.6 Hz, chloro-benzamide 2H), 2.98
(s, 6H), 1.65 (d, J = 4.8 Hz, 3H). 45 6-(2-furylmethyl)-4- 1H NMR
(400 MHz, CDCl3): .delta. 10.20 (s, 1 H), 290 phenyl-1H- 7.57-7.54
(m, 2 H), 7.47-7.44 (m, 2 H), pyrrolo[2,3- 7.38-7.35 (m, 2 H),
7.29-7.26 (m, 1 H), 7.13 (s, 1 H), c]pyridin-7-one 6.55-6.54 (m, 1
H), 6.43-6.43 (m, 1 H), 6.35-6.33 (m, 1 H), 5.31 (s, 2 H). 46
3-(6-butyl-7-oxo-1H- .sup.1H NMR (400 MHz, DMSO-d6): .delta. 11.98
(s, 1 H), 321 pyrrolo[2,3- 7.86-7.84 (m, 1 H), 7.74 (d, J = 2.4 Hz,
1 H), c]pyridin-4-yl)-4- 7.30-7.25 (m, 3 H), 6.04 (t, J = 2.4 Hz, 1
H), 3.99 (t, J = 7.2 Hz, methoxy-benzonitrile 2 H), 3.82 (s, 3 H),
1.69-1.65 (m, 2 H), 1.35-1.30 (m, 2 H), 0.93-0.90 (t, J = 7.2, 3
H). 47 3-[6-(2- .sup.1 H NMR (400 MHz, DMSO-d6): .delta. 11.99 (s,
1 H), 333 cyclopropylethyl)-7- 7.86-7.84 (m, 1 H), 7.73 (s, 1 H),
7.30-7.25 (m, 3 oxo-1H-pyrrolo[2,3- H), 6.03-6.02 (m, 1 H),
4.07-4.04 (m, 2 H), 3.81 (s, c]pyridin-4-yl]-4- 3 H), 1.61-1.56 (m,
2 H), 0.74-0.67 (m, 1 H), methoxy-benzonitrile 0.41-0.39 (m, 2 H),
0.09-0.01 (m, 2 H). 48 6-but-3-enyl-4-[3,4- 1H NMR (400 MHz,
DMSO-d6) .delta. 12.18 (s, 1H), 414 difluoro-5- 7.72 (ddd, J =
11.7, 7.5, 2.2 Hz, 1H), 7.48 (s, 1H), (morpholine-4- 7.45-7.36 (m,
2H), 6.45 (d, J = 2.8 Hz, 1H), carbonyl)phenyl]-1H- 5.86 (ddt, J =
17.0, 10.2, 6.7 Hz, 1H), 5.14-4.99 (m, pyrrolo[2,3- 2H), 4.10 (t, J
= 7.3 Hz, 2H), 3.68 (m, 4H), 3.57 (m, c]pyridin-7-one J = 4.8 Hz,
2H), 3.35 (m, J = 4.7 Hz, 2H). 49 6-but-3-enyl-4-[3- .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 7.48-7.43 (m, 2 H), 410 fluoro-5-(3-
7.43 (d, J = 3.2 Hz, 1 H), 7.38 (s, 1 H), methylmorpholine-4-
7.39-7.17 (m, 1 H), 6.55 (d, J = 3.2 Hz, 1 H), 5.95-5.88 (m, 1
carbonyl)phenyl]-1H- H), 5.12-5.05 (m, 2 H), 4.22 (t, J = 7.2 Hz, 2
H), pyrrolo[2,3- 3.92-3.90 (m, 1 H), 3.72-3.71 (m, 2 H),
c]pyridin-7-one 3.36-3.32 (m, 4 H), 2.62-2.57 (m, 2 H), 1.42 (d, J
= 6.8 Hz, 3 H). 50 3-(6-but-3-enyl-7- .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 12.21 (s, 1 H), 403.3 oxo-1H-pyrrolo[2,3- 8.09 (s,
1 H), 7.90 (s, 1 H), 7.83 (s, 1H), 7.58 (s, 1 c]pyridin-4-yl)-5-
H), 7.38 (s, 1 H), 6.46 (s, 1 H), 5.85-5.81 (m, 1 H),
(morpholine-4- 5.08-4.99 (m, 2 H), 4.11-4.08 (m, 2 H),
carbonyl)benzonitrile 3.63-3.53 (m, 4 H), 3.36-3.26 (m, 4 H),
2.48-2.46 (m, 2 H). 51 6-[(E)-but-2-enyl]-4- 1H NMR (400 MHz,
DMSO-d6) .delta. 12.22 (s, 1H), 412 [3-chloro-4- 7.70 (d, J = 1.7
Hz, 1H), 7.65 (dd, J = 7.9, 1.7 Hz, (morpholine-4- 1H), 7.50-7.43
(m, 2H), 7.39 (d, J = 2.8 Hz, 1H), carbonyl)phenyl]-1H- 6.48 (d, J
= 2.8 Hz, 1H), 5.74-5.59 (m, 2H), pyrrolo[2,3- 4.60 (d, J = 4.9 Hz,
2H), 3.75-3.62 (m, 4H), c]pyridin-7-one 3.61-3.53 (m, 2H),
3.24-3.16 (m, 2H), 1.68-1.60 (m, 3H). 52 6-[(E)-but-2-enyl]-4- 1H
NMR (400 MHz, DMSO-d6) .delta. 12.18 (s, 1H), 396 [3-chloro-4- 7.68
(d, J = 1.7 Hz, 1H), 7.63 (dd, J = 7.9, 1.7 Hz, (pyrrolidine-1-
1H), 7.47 (s, 1H), 7.44 (d, J = 6.1 Hz, 1H), 7.39 (d, J = 2.8 Hz,
carbonyl)phenyl]-1H- 1H), 6.47 (d, J = 2.8 Hz, 1H), pyrrolo[2,3-
5.74-5.60 (m, 2H), 4.60 (d, J = 4.9 Hz, 2H), 3.57-3.42 (m,
c]pyridin-7-one 2H), 3.24-3.10 (m, 3H), 1.97-1.74 (m, 5H),
1.70-1.58 (m, 3H). 53 6-but-3-enyl-4-[3- 1H NMR (400 MHz, DMSO-d6)
.delta. 12.18 (s, 1H), 396 fluoro-5- 7.52 (s, 1H), 7.45 (t, J = 1.5
Hz, 1H), (morpholine-4- 7.40-7.36 (m, 1H), 7.23 (m, J = 8.8, 2.5,
1.3 Hz, 1H), 6.45 (d, carbonyl)phenyl]-1H- J = 2.8 Hz, 1H),
6.00-5.75 (m, 1H), pyrrolo[2,3- 5.21-4.92 (m, 2H), 4.12 (t, J = 7.3
Hz, 2H), 3.62 (m, 8H). c]pyridin-7-one 54 6-but-3-enyl-4-[4- 1H NMR
(400 MHz, DMSO-d6) .delta. 12.14 (s, 1H), 396 fluoro-3- 7.71 (m, J
= 8.6, 5.1, 2.4 Hz, 1H), 7.58 (m, J = 6.4, (morpholine-4- 2.4 Hz,
1H), 7.47-7.33 (m, 3H), 6.41 (d, J = 2.9 Hz, carbonyl)phenyl]-1H-
1H), 5.95-5.78 (m, 1H), 5.15-4.96 (m, 2H), pyrrolo[2,3- 4.20-4.02
(m, 2H), 3.67 (m, 4H), 3.56 (m, J = 5.1 Hz, c]pyridin-7-one 4H),
2.49 (m, J = 4.7 Hz, 2H).
Example 55
6-(but-3-en-1-yl)-4-(3-(difluoromethoxy)-5-(morpholine-4-carbonyl)phenyl)--
1H-pyrrolo[2,3-c]pyridin-7(6H)-one
##STR00157## Step 1:
(3-bromo-5-hydroxyphenyl)(morpholino)methanone
##STR00158##
To a solution of 3-bromo-5-hydroxybenzoic acid (2.00 g, 9.2 mmol)
in DMF (20 mL) was added HATU (3.89 g, 10.2 mmol), DIPEA (1.32 g,
10.2 mmol) and morpholine (887 mg, 10.2 mmol). The reaction mixture
was stirred at room temperature for 10 h, at which time LCMS showed
the completion of the reaction. The mixture was poured into water
(40 mL) and extracted with ethyl acetate (50 mL.times.3). The
combined organic layers were concentrated under reduced pressure.
The residue was purified by flash chromatography (Petroleum
ether/ethyl acetate=1:2) to give the title compound (900 mg, 31%
yield) as a white solid.
Step 2:
(3-bromo-5-(difluoromethoxy)phenyl)(morpholino)methanone
##STR00159##
To a solution of (3-bromo-5-hydroxyphenyl)(morpholino)methanone
(900 mg, 3.2 mmol) in DMF (20 mL)/H.sub.2O (5 mL) was added
K.sub.2CO.sub.3 (877 mg, 6.3 mmol) and sodium
2-chloro-2,2-difluoroacetate (966 mg, 6.3 mmol). The reaction
mixture was heated at 100.degree. C. for 2 h, at which time LCMS
showed the completion of the reaction. After cooled, the mixture
was poured into water (600 mL) and the resulting mixture was
extracted with ethyl acetate (50 mL.times.3). The combined organic
layers were concentrated under reduced pressure. The residue was
purified by flash chromatography (Petroleum ether/ethyl
acetate=1:1) to give the title compound (400 mg, 38% yield) as a
yellow solid.
Step 3:
(3-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl-
)(morpholino)methanone
##STR00160##
A mixture of
(3-bromo-5-(difluoromethoxy)phenyl)(morpholino)methanone (400 mg,
1.19 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (455
mg, 1.79 mmol), potassium acetate (175 mg, 1.79 mmol) and
Pd(dppf)Cl.sub.2 (73 mg, 0.1 mmol) in dioxane (25 mL) was heated at
120.degree. C. under N.sub.2 for 5 h. After completion, the
reaction mixture was concentrated under reduced pressure. The
residue was dissolved in ethyl acetate (60 mL) and washed with
water (30 mL.times.2). The separated organic layer was concentrated
under reduced pressure. The crude product was purified by flash
chromatography (Petroleum ether/ethyl acetate=1:1) to give the
title compound (300 mg, 66% yield) as a yellow oil.
Step 4:
6-(but-3-en-1-yl)-4-(3-(difluoromethoxy)-5-(morpholine-4-carbonyl)phenyl)--
1H-pyrrolo[2,3-c]pyridin-7(6H)-one
##STR00161##
In a similar procedure as shown in Example A06, the title compound
was prepared in 13.8% yield from
(3-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pheny-
l)(morpholino)methanone and 4-bromobut-1-ene. .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 12.18 (s, 1H), 7.55-7.36 (m, 3H), 7.18-7.15 (m,
1H), 6.42 (s, 1H), 5.87-5.80 (m, 1H), 5.07-4.99 (m, 2H), 4.11-4.08
(m, 2H), 3.63-3.53 (m, 4H), 3.36-3.26 (m, 4H), 2.48-2.46 (m, 2H).
LCMS M/Z (M+H) 444.
Example 56
6-but-3-enyl-4-[7-(morpholine-4-carbonyl)-3H-benzimidazol-5-yl]-1H-pyrrolo-
[2,3-c]pyridin-7-one
##STR00162## Step 1
4-bromo-6-(but-3-en-1-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
##STR00163##
To a solution of
4-bromo-1-(p-tolylsulfonyl)-6H-pyrrolo[2,3-c]pyridin-7-one (10.0 g,
27.23 mmol) (Intermediate A) in DMF (150 mL) were added cesium
carbonate (17.8 g, 54.46 mmol) and 4-bromobut-1-ene (4.8 g, 35.40
mmol). After addition, the mixture was stirred at ambient
temperature for 16 h, at which time LCMS indicated the reaction had
gone to completion. The solid was removed by filtration and the
filtrate was concentrated under reduce pressure. The residue was
dissolved in H.sub.2O (100 mL) and extracted with ethyl acetate
(3.times.100 mL). The combined organic layers were concentrated
under reduced pressure and the crude product was purified by silica
gel chromatography column (Hexanes/ethyl acetate=5:1) to give title
compound (6.0 g, 52% yield) as a colorless oil. .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. 8.05-8.04 (m, 1H), 7.94-7.89 (m, 1H),
7.76 (s, 1H), 7.45-7.35 (m, 2H), 6.58-6.57 (m, 1H), 5.73-5.66 (m,
1H), 4.92-4.84 (m, 2H), 3.93-3.89 (m, 2H), 2.39 (s, 3H), 2.36-2.27
(m, 2H).
Step 2
(2-amino-3-nitrophenyl)(morpholino)methanone
##STR00164##
To a solution of morpholine (2.4 g, 27.45 mmol) in DMF (80 mL) was
added 2-amino-3-nitrobenzoic acid (5.0 g, 27.45 mmol), HATU (12.5
g, 32.94 mmol) and N-ethyl-N-isopropylpropan-2-amine (10 mL). The
reaction mixture was stirred at ambient temperature for 15 h, at
which time LCMS indicated that the reaction had gone to completion.
The mixture was concentrated under reduced pressure. The residue
was diluted with ethyl acetate (100 mL) and washed with water
(2.times.50 mL). The organic solution was concentrated under
reduced pressure and the residue was purified by silica gel
chromatography (Hexanes/ethyl acetate=3:1) to give the title
compound (5.0 g, 73% yield) as a yellow solid.
Step 3
(2-amino-5-bromo-3-nitrophenyl)(morpholino)methanone
##STR00165##
To a solution of (2-amino-3-nitrophenyl)(morpholino)methanone (5.0
g, 19.90 mmol) in acetic acid (50 mL) was added Br.sub.2 (3.82 g,
23.88 mmol). The reaction mixture was stirred at 0.degree. C. for
30 min, at which time LCMS indicated that the reaction had gone to
completion. The reaction mixture was poured into ice-cold water (30
mL). The resulting precipitate was collected by filtration and
dried under reduced pressure to give the title compound (5.0 g, 76%
yield) as yellow solid.
Step 4
(2,3-diamino-5-bromophenyl)(morpholino)methanone
##STR00166##
To a solution of
(2-amino-5-bromo-3-nitrophenyl)(morpholino)methanone (5.0 g, 15.15
mmol) in EtOH/H.sub.2O (5:1, 100 mL) was added NH.sub.4Cl (4.1 g,
75.73 mmol) and Fe (4.2 g, 75.73 mmol). The reaction mixture was
heated at reflux for 15 h, at which time LCMS indicated that the
reaction had gone to completion. The solid was removed by
filtration and the filtrate concentrated under reduced pressure.
The residue was dissolved in ethyl acetate (100 mL) and washed with
brine (2.times.40 mL). The separated organic layer was concentrated
to give the crude title compound (4.2 g, 92% yield) as a yellow
oil.
Step 5
(6-bromo-1H-benzo[d]imidazol-4-yl)(morpholino)methanone
##STR00167##
To a solution of
(2-amino-5-bromo-3-nitrophenyl)(morpholino)methanone (4.2 g, 12.72
mmol) in DMF (40 mL) was added triethoxymethane (2.8 g, 19.08 mmol)
and 4-methylbenzenesulfonic acid (220 mg, 1.27 mmol). After
addition, the reaction mixture was stirred at ambient temperature
for 15 h, at which time LCMS indicated that the reaction had gone
to completion. The solvent was evaporated under reduced pressure,
and the residue was diluted with water (40 mL). The mixture was
extracted with ethyl acetate (3.times.50 mL). The combined organic
extracts were concentrated under reduced pressure. The crude
product was purified by silica gel chromatography
(dichloromethane/methanol=10:1) to give the title compound (3.0 g,
76% yield) as a brown solid.
Step 6
(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-4-yl)(mo-
rpholino)methanone
##STR00168##
To a solution of
(6-bromo-1H-benzo[d]imidazol-4-yl)(morpholino)methanone (3.0 g,
9.67 mmol) in DMF (50 mL) was slowly added sodium hydride (60%, 464
mg, 11.61 mmol) at 0.degree. C. After addition, the mixture was
stirred at 0.degree. C. for 1 h, and then
(2-(chloromethoxy)ethyl)trimethylsilane (1.9 g, 11.61 mmol) was
added dropwise. The resulting mixture was stirred at ambient
temperature for another 2 h, at which time LCMS indicated that the
reaction had gone to completion. The reaction was quenched by
addition of saturated aqueous ammonium chloride (50 mL), and then
extracted with ethyl acetate (3.times.50 mL). The combined organic
extracts were concentrated under reduced pressure. The crude
product was purified by silica gel chromatography (Hexanes/ethyl
acetate=1:1) to give the title compound (3.0 g, 70% yield) as a
yellow solid.
Step 7
Morpholino(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethy-
lsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-4-yl)methanone
##STR00169##
A mixture of
(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-4-yl)(m-
orpholino)methanone (3.0 g, 6.81 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.6 g,
13.62 mmol), potassium acetate (1.7 g, 17.64 mmol) and
Pd(dppf)Cl.sub.2 (0.5 g, 0.68 mmol) in dioxane (45 mL) was heated
at 110.degree. C. under microwave conditions for 45 min, at which
time LCMS indicated the reaction had gone to completion. The
mixture was concentrated under reduced pressure. The residue was
dissolved in ethyl acetate (80 mL), washed with water (2.times.50
mL), and concentrated to give the crude title compound (1.35 g, 41%
yield) as a brown oil.
Step 8
6-(but-3-en-1-yl)-4-(4-(morpholine-4-carbonyl)-1-((2-(trimethylsilyl)ethox-
y)methyl)-1H-benzo[d]imidazol-6-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-
-one
##STR00170##
A mixture of
morpholino(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimeth-
ylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-4-yl)methanone (450 mg,
0.92 mmol),
4-bromo-6-(but-3-en-1-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-o-
ne (389 mg, 0.92 mmol), Pd(dppf)Cl.sub.2 (66 mg, 0.09 mmol) and
cesium carbonate (601 mg, 1.85 mmol) in dioxane/H.sub.2O (10 mL,
4:1) was heated at 110.degree. C. under microwave conditions for 45
min, at which time LCMS indicated the reaction had gone to
completion. The mixture was concentrated under reduced pressure.
The residue was dissolved in ethyl acetate (30 mL), washed with
water (2.times.20 mL), concentrated under reduced pressure. The
residue was purified by silica gel chromatography (Hexanes/ethyl
acetate=2:1) to give the title compound (500 mg, 77% yield) as a
yellow solid.
Step 9
6-but-3-enyl-4-[7-(morpholine-4-carbonyl)-3H-benzimidazol-5-yl]-1H-pyrrolo-
[2,3-c]pyridin-7-one
##STR00171##
To a solution of
6-(but-3-en-1-yl)-4-(4-(morpholine-4-carbonyl)-1-((2-(trimethylsilyl)etho-
xy)methyl)-1H-benzo[d]imidazol-6-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H-
)-one (500 mg, 0.71 mmol) in dioxane/H.sub.2O (10 mL, 1:1) was
added sodium hydroxide (57 mg, 1.42 mmol). The reaction mixture was
heated at 80.degree. C. for 3 h, at which time LCMS indicated the
reaction had gone to completion. The mixture was concentrated under
reduced pressure. The residue was diluted with ethyl acetate (30
mL), washed with water (2.times.20 mL), and concentrated under
reduced pressure to give the crude
6-(but-3-en-1-yl)-4-(4-(morpholine-4-carbonyl)-1-((2-(trimethylsily-
l)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)-1H-pyrrolo[2,3-c]pyridin-7(6H)--
one (350 mg, 90% yield).
To a solution of the above crude in dichloromethane (15 mL) was
added trifluoroacetic acid (15 mL). After addition, the reaction
mixture was stirred at ambient temperature for 3 h, at which time
LCMS indicated that the reaction had gone to completion. The
reaction mixture was concentrated under reduced pressure. The crude
was purified by reverse phase chromatography (acetonitrile
13-33%/0.1% HCl in water) to give the title compound (11 mg, 5%
yield). .sup.1HNMR (400 MHz, CD.sub.3OD): .delta. 9.58 (s, 1H),
8.16 (s, 1H), 7.91 (s, 1H), 7.48 (s, 2H), 6.57 (s, 1H), 5.97-5.88
(m, 1H), 5.09 (t, J=10.4 Hz, 2H), 4.26 (t, J=7.2 Hz, 2H), 4.02-3.48
(m, 8H), 2.65-2.57 (m, 2H); LCMS M/Z (M+H) 418.
Example 57 and 58
6-but-3-enyl-4-[3-methyl-7-(morpholine-4-carbonyl)benzimidazol-5-yl]-1H-py-
rrolo[2,3-e]pyridin-7-one and
6-but-3-enyl-4-[1-methyl-7-(morpholine-4-carbonyl)benzimidazol-5-yl]-1H-p-
yrrolo[2,3-c]pyridin-7-one
##STR00172## Step 1
6-(but-3-en-1-yl)-4-(4-(morpholine-4-carbonyl)-1H-benzo[d]imidazol-6-yl)-1-
-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
##STR00173##
To a solution of
6-(but-3-en-1-yl)-4-(4-(morpholine-4-carbonyl)-1-((2-(trimethylsilyl)etho-
xy)methyl)-1H-benzo[d]imidazol-6-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H-
)-one (500 mg, 0.71 mmol) in dichloromethane (10 mL) was added
trifluoroacetic acid (10 mL). After addition, the reaction mixture
was stirred at ambient temperature for 3 h, at which time LCMS
indicated that the reaction had gone to completion. The reaction
mixture was concentrated under reduced pressure to give the crude
title compound (400 mg, 98% yield) as a yellow oil.
Step 2
6-but-3-enyl-4-[3-methyl-7-(morpholine-4-carbonyl)benzimidazol-5-yl]-1H-py-
rrolo[2,3-c]pyridin-7-one and
6-but-3-enyl-4-[1-methyl-7-(morpholine-4-carbonyl)benzimidazol-5-yl]-1H-p-
yrrolo[2,3-c]pyridin-7-one
##STR00174##
To a stirred and cooled (0.degree. C.) solution of
(6-bromo-1H-benzo[d]imidazol-4-yl) (morpholino)methanone (500 mg,
0.87 mmol) in DMF (10 mL) was slowly added sodium hydride (60%, 42
mg, 0.92 mmol). After addition, the mixture was stirred at
0.degree. C. for 1 h, and then iodomethane (149 mg, 0.92 mmol) was
added. The resulting mixture was stirred at ambient temperature for
2 h, at which time LCMS indicated that the reaction had gone to
completion. The reaction was quenched by addition of saturated
aqueous ammonium chloride (10 mL), and then extracted with ethyl
acetate (3.times.20 mL). The combined organic extracts were
concentrated under reduced pressure. The residue was purified by
silica gel chromatography (Hexanes/ethyl acetate=1:1) to give the
mixture of the methylated regio-isomers (250 mg, 49% yield) as a
brown solid.
To a solution of the above regio-isomers (250 mg, 0.43 mmol) in
dioxane/H.sub.2O (10 mL, 1:1) was added sodium hydroxide (34 mg,
0.86 mmol). The reaction mixture was heated at 80.degree. C. for 3
h, at which time LCMS indicated the reaction had gone to
completion. The reaction mixture was concentrated under reduced
pressure and partitioned between dichloromethane (40 mL) and water
(30 mL). The separated organic layer was concentrated under reduced
pressure, and the residue was purified by reverse phase
chromatography (acetonitrile 18-48%/0.1% NH.sub.4OH in water) to
the title compounds as white solids.
Example 57
(6.3 mg, 3% yield). .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 9.59
(s, 1H), 8.26 (s, 1H), 7.95 (s, 1H), 7.53-7.49 (m, 2H), 7.62 (d,
J=2.8 Hz, 1H), 5.98-5.89 (m, 1H), 5.13-5.06 (m, 2H), 4.29-4.26 (m,
4H), 4.02-3.46 (m, 8H), 2.66-2.61 (m, 2H). LCMS M/Z (M+H) 432.
Example 58
(11 mg, 6% yield). .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 9.54
(s, 1H), 8.14 (s, 1H), 7.87 (s, 1H), 7.48 (s, 2H), 6.55 (d, J=2.8
Hz, 1H), 5.96-5.90 (m, 1H), 5.13-5.06 (m, 2H), 4.27-4.24 (m, 2H),
4.14 (s, 3H), 4.04-3.54 (m, 8H), 2.64-2.59 (m, 2H). LCMS M/Z (M+H)
432.
Example 59
6-but-3-enyl-4-[3-ethyl-7-(morpholine-4-carbonyl)benzimidazol-5-yl]-1H-pyr-
rolo[2,3-c]pyridin-7-one
##STR00175##
In a similar procedure as shown in Example 02, the title compound
was prepared in 4% yield from iodoethane. .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. 8.32 (s, 1H), 7.87 (s, 1H), 7.54 (s, 1H), 7.40
(s, 1H), 7.35 (s, 1H), 6.58 (s, 1H), 5.93-5.87 (m, 1H), 5.10-5.02
(m, 2H), 4.43-4.38 (m, 2H), 4.21 (t, J=7.2 Hz, 2H), 3.88-3.81 (m,
4H), 3.62-3.56 (m, 2H), 3.42-3.35 (m, 2H), 2.61-2.56 (m, 2H), 1.55
(t, J=7.2 Hz, 3H). LCMS M/Z (M+H) 446.
Example 60
6-but-3-enyl-4-[6-(morpholine-4-carbonyl)-1H-benzimidazol-4-yl]-1H-pyrrolo-
[2,3-c]pyridin-7-one
##STR00176## Step 1
Methyl 3,4-diamino-5-bromobenzoate
##STR00177##
A mixture of methyl 4-amino-3-bromo-5-nitrobenzoate (1.0 g, 3.64
mmol) and SnCl.sub.2.2H.sub.2O (1.6 g, 7.27 mmol) in ethyl acetate
(30 mL) was heated at 90.degree. C. for 18 h, at which time LCMS
indicated the reaction had gone to completion. After cooled, the
mixture was diluted with water (30 mL), and extracted with ethyl
acetate (3.times.30 mL). The combined organic layers were
concentrated under reduced pressure to give the crude title
compound (850 mg, 95% yield) as yellow solid. .sup.1HNMR (400 MHz,
CDCl.sub.3): .delta. 7.74 (d, J=1.6 Hz, 1H), 7.35 (s, 1H), 4.25
(br., s, 2H), 3.86 (s, 3H), 3.50 (br., s, 2H).
Step 2
Methyl 4-bromo-1H-benzo[d]imidazole-6-carboxylate
##STR00178##
To a solution of methyl 3,4-diamino-5-bromobenzoate (850 mg, 3.47
mmol) in THF (30 mL) were added triethoxymethane (1.04 g, 7.0 mmol)
and TsOH.H.sub.2O (66 mg, 0.35 mmol). The resulting mixture was
stirred at room temperature for 5 h, at which time LCMS indicated
that the reaction had gone to completion. The solvent was
evaporated under reduced pressure. The residue was diluted with
water (30 mL) and extracted with ethyl acetate (3.times.30 mL). The
combined organic layers were concentrated under reduced pressure to
give the crude title compound (820 mg, 93% yield) as pale white
solid. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.40 (s, 1H),
8.22 (s, 2H), 3.97 (s, 3H).
Step 3
(6-(methoxycarbonyl)-1H-benzo[d]imidazol-4-yl)boronic acid
##STR00179##
A mixture of methyl 4-bromo-1H-benzo[d]imidazole-6-carboxylate (820
mg, 3.21 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.15
g, 4.51 mmol), Pd(dppf)Cl.sub.2 (234 mg, 0.32 mmol) and potassium
acetate (631 mg, 6.44 mmol) in dioxane (30 mL) was heated at
120.degree. C. under N.sub.2 atmosphere for 16 h, at which time
LCMS indicated that the reaction had gone to completion. After
cooled, the mixture was filtered through a short celite pad and
rinsed with dioxane (20 mL). The filtrate was concentrated under
reduced pressure. The residue was diluted with water (50 mL),
extracted with ethyl acetate (3.times.50 mL). The combined organic
layers were concentrated under reduced pressure to give the crude
product as a brown solid (650 mg, 92% yield). LCMS M/Z (M+H)
220.8.
Step 4
Methyl
4-(6-(but-3-en-1-yl)-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyr-
idin-4-yl)-1H-benzo[d]imidazole-6-carboxylate
##STR00180##
A mixture of
4-bromo-6-(but-3-en-1-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
(421 mg, 1.00 mmol),
(6-(methoxycarbonyl)-1H-benzo[d]imidazol-4-yl)boronic acid (330 mg,
1.5 mmol), cesium carbonate (652 mg, 2.0 mmol) and Pd(dppt)Cl.sub.2
(73 mg, 0.10 mmol) in dioxane/H.sub.2O (5/1, 30 mL) were heated at
100.degree. C. under N.sub.2 for 3 h, at which time LCMS indicated
that the reaction had gone to completion. The solvent was
evaporated under reduced pressure. The residue was diluted with
water (30 mL) and extracted with ethyl acetate (3.times.30 mL). The
combined organic layers were concentrated under reduced pressure.
The residue was purified by silica gel chromatography
(DCM/Methanol=99:1 to 16:1) to give the title compound as a white
solid (400 mg, 77% yield). LCMS M/Z (M+H) 516.
Step 5
4-(6-(but-3-en-1-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-1H-b-
enzo[d]imidazole-6-carboxylic acid
##STR00181##
To a solution of methyl
4-(6-(but-3-en-1-yl)-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-
-yl)-1H-benzo[d]imidazole-6-carboxylate (400 mg, 0.77 mmol) in
methanol (10 mL) was added a solution of sodium hydroxide (1 N in
water, 2.0 mL, 2.0 mmol) at room temperature. The resulting mixture
was heated at 100.degree. C. for 2 h, at which time LCMS indicated
that the reaction had gone to completion. After cooled, the mixture
was adjusted to pH=3-4 by additional of 1 N aqueous HCl. The
resulting mixture was extracted with ethyl acetate (3.times.30 mL).
The combined organic layers were concentrated under reduced
pressure to give the crude title compound (200 mg, 74% yield) as a
white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 12.94
(br. s, 1H), 12.16 (s, 1H), 8.84 (s, 1H), 8.19 (s, 1H), 8.06 (s,
1H), 7.67 (s, 1H), 7.45 (d, J=8.0 Hz, 0.5H), 7.34 (s, 1H), 7.07 (d,
J=7.6 Hz, 0.5H), 6.24 (s, 1H), 5.87-5.80 (m, 1H), 5.08-4.97 (m,
2H), 4.13-4.09 (m, 2H), 2.50-2.48 (m, 1H), 2.25 (s, 1H).
Step 6
6-but-3-enyl-4-[6-(morpholine-4-carbonyl)-1H-benzimidazol-4-yl]-1H-pyrrolo-
[2,3-c]pyridin-7-one
##STR00182##
A mixture of
4-(6-(but-3-en-1-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-yl)-1H-
-benzo[d]imidazole-6-carboxylic acid (100 mg, 0.28 mmol),
morpholine (73 mg, 0.84 mmol), HATU (141 mg, 0.37 mmol) and
N-ethyl-N-isopropylpropan-2-amine (72 mg, 0.56 mmol) in DMF (10 mL)
was heated at 60.degree. C. for 8 h, at which time LCMS indicated
that the reaction had gone to completion. The solvent was
evaporated under reduced pressure. The residue was dissolved in
dichloromethane (50 mL), washed with brine (2.times.20 mL), and
concentrated under reduced pressure. The crude product was purified
by reverse phase chromatography (acetonitrile 10-40%/0.1% HCl in
water) to give the title compound as a white solid (25 mg, 21%
yield). .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 9.56 (s, 1H),
7.97 (d, J=4.0 Hz, 1H), 7.78 (s, 1H), 7.58 (s, 1H), 7.45 (d, J=2.8
Hz, 1H), 6.28 (d, J=2.8 Hz, 1H), 5.94-5.88 (m, 1H), 5.15-5.05 (m,
2H), 4.27 (t, J=7.2 Hz, 2H), 3.93-3.47 (m, 8H), 2.65-2.59 (m, 2H).
LCMS M/Z (M+H) 418.
Example 61
4-(6-(but-3-en-1-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N,N--
dimethyl-1H-benzo[d]imidazole-6-carboxamide
##STR00183##
In a similar procedure as shown in Example 04, the title compound
was prepared in 33% yield from dimethylamine hydrochloride. .sup.1H
NMR (400 MHz, CD.sub.3OD): .delta. 9.54 (s, 1H), 7.96 (d, J=1.6 Hz,
1H), 7.78 (d, J=1.6 Hz, 1H), 7.55 (s, 1H), 7.44 (d, J=2.8 Hz, 1H),
6.29 (d, 2.8 Hz, 1H), 5.95-5.88 (m, 1H), 5.14-5.04 (m, 2H), 4.26
(t, J=7.2 Hz, 2H), 3.20 (s, 3H), 3.12 (s, 3H), 2.65-2.59 (m, 2H).
LCMS M/Z (M+H) 376.
Example 62
6-but-3-enyl-4-[1-methyl-6-(morpholine-4-carbonyl)benzimidazol-4-yl]-1H-py-
rrolo[2,3-e]pyridin-7-one
##STR00184## Step 1
6-(but-3-en-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl--
1H-pyrrolo[2,3-e]pyridin-7(6H)-one
##STR00185##
A mixture of
4-bromo-6-(but-3-en-1-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
(5.0 g, 11.87 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (7.5 g,
29.67 mmol), potassium acetate (2.3 g, 23.74 mmol) and
Pd(dppf)Cl.sub.2 (870 mg, 1.19 mmol) in dioxane (50 mL) was heated
at 120.degree. C. under microwave conditions for 1 h, at which time
LCMS indicated the reaction had gone to completion. The mixture was
concentrated under reduced pressure. The residue was diluted with
H.sub.2O (20 mL), extracted with ethyl acetate (3.times.20 mL). The
combined organic layers were concentrated under reduced pressure
and the crude product was purified by silica gel chromatography
column (Hexanes/ethyl acetate=2:1) to give the title compound (3.5
g, 44% yield) as a pale yellow oil.
Step 2
Methyl 4-bromo-1-methyl-1H-benzo[d]imidazole-6-carboxylate
##STR00186##
To a solution of methyl 4-bromo-1H-benzo[d]imidazole-6-carboxylate
(3.8 g, 14.9 mmol) in DMF (80 mL) was added potassium carbonate
(6.2 g, 44.69 mmol) and CH.sub.3I (6.3 g, 44.69 mmol). After
addition, the reaction mixture was stirred at 30.degree. C. for 6
h, at which time LCMS indicated the reaction had gone to
completion. The solvent was removed by concentration under reduced
pressure. The residue was diluted with H.sub.2O (30 mL), extracted
with ethyl acetate (3.times.30 mL). The combined organic layers
were concentrated to give the title compound (1.8 g, 45% yield) as
a yellow solid.
Step 3
Methyl
4-(6-(hut-3-en-1-yl)-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyr-
idin-4-yl)-1-methyl-1H-benzo[d]imidazole-6-carboxylate
##STR00187##
A mixture of methyl
4-bromo-1-methyl-1H-benzo[d]imidazole-6-carboxylate (500 mg, 1.86
mmol),
6-(but-3-en-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-
-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (1.04 g, 2.23 mmol), cesium
carbonate (908 mg, 2.79 mmol) and Pd(dppf)Cl.sub.2 (136 mg, 0.19
mmol) in dioxane/H.sub.2O (5:1, 18 mL) was heated at 120.degree. C.
under microwave conditions for 40 min, at which time LCMS indicated
the reaction had gone to completion. The solvent was evaporated
under reduced pressure. The residue was diluted with H.sub.2O (50
mL) and extracted with ethyl acetate (3.times.50 mL). The combined
organic layers were concentrated under reduced pressure. The
residue was purified by silica gel chromatography column
(Hexanes/ethyl acetate=1:2) to give the title compound (350 mg, 36%
yield) as a yellow solid.
Step 4
4-(6-(but-3-en-1-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-1-me-
thyl-1H-benzo[d]imidazole-6-carboxylic acid
##STR00188##
To a solution of methyl
4-(6-(but-3-en-1-yl)-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-
-yl)-1-methyl-1H-benzo[d]imidazole-6-carboxylate (350 mg, 0.66
mmol) in Methanol/H.sub.2O (15/3 mL) was added sodium hydroxide
(132 mg, 3.30 mmol). The mixture was heated at 80.degree. C. for 16
h, at which time LCMS indicated the reaction had gone to
completion. The mixture was concentrated under reduced pressure and
the residue was diluted with H.sub.2O (8 mL). The solution was
adjusted to pH=5-6 by addition of 2 N aqueous HCl. The resulting
precipitate was collected by filtration, washed with water and
dried under reduced pressure to give the title compound (220 mg,
92% yield) as a yellow solid.
Step 5:
6-but-3-enyl-4-[1-methyl-6-(morpholine-4-carbonyl)benzimidazol-4-yl]-1H-py-
rrolo[1,3-c]pyridin-7-one
##STR00189##
To a solution of
4-(6-(but-3-en-1-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-1-m-
ethyl-1H-benzo[d]imidazole-6-carboxylic acid (220 mg, 0.61 mmol) in
DMF (5 mL) was added triethylamine (123 mg, 1.21 mmol), HATU (460
mg, 1.21 mmol) and morpholine (106 mg, 1.21 mmol). The resulting
mixture was stirred at 30.degree. C. for 16 h, at which time LCMS
indicated the reaction had gone to completion. The reaction mixture
was concentrated under reduced pressure and the crude product was
purified by reverse phase chromatography (acetonitrile 19%/0.1%
NH4OH in water) to give the title compound (86 mg, 33% yield) as a
white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 12.09 (s,
1H), 8.33 (s, 1H), 7.84 (s, 1H), 7.64 (s, 1H), 7.46 (s, 1H),
7.35-7.34 (m, 1H), 6.37 (s, 1H), 5.93-5.84 (m, 1H), 5.12-5.07 (m,
2H), 5.03-5.00 (m, 1H), 4.15-4.11 (m, 2H), 4.08 (s, 3H), 3.63-3.57
(m, 8H), 2.46-2.44 (m, 2H). LCMS M/Z (M+H) 432.
Example 63
3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N-cyclopropyl-4-
-methoxy-benzamide
##STR00190## Step 1:
4-bromo-6-[(E)-but-2-enyl]-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridin-7-one
##STR00191##
Title compound was prepared in the same manner as described in
Example 1, Step 1.
Step 2:
3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-4-methoxy-benzo-
ic acid
##STR00192##
Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)
(0.05 equiv., 0.24 mmol) was added to a mixture of
4-bromo-6-[(E)-but-2-enyl]-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridin-7-one
(4.75 mmol) and 3-borono-4-methoxy-benzoic acid (1.25 equiv., 5.9
mmol) in 1,4-dioxane (14 mL) and potassium phosphate tribasic (2M
in water, 3 equiv., 14.24 mmol). The reaction was heated at
90.degree. C. for 2 h. After cooling, the reaction was diluted with
water (20 mL) and extracted with ethyl acetate (3.times.20 mL). The
combined organic extracts were dried over sodium sulfate and
concentrated under reduced pressure. The residue was purified by
silica gel chromatography (30-70% ethyl acetate/heptanes) to afford
the expected tosyl intermediate.
The intermediate was taken up in methanol (10 mL) and 10 M
potassium hydroxide in water (1 mL) was added. The reaction was
heated to 45.degree. C. for 2 h and then the methanol was removed
under reduced pressure. The residue was dissolved in water 10 mL
and the aqueous layer was extracted with diethyl ether. The aqueous
solution was adjusted to pH 2 using 1 M hydrochloric acid and the
resulting precipitate was collected by filtration. The crude
product was triturated with hot isopropanol, to afford the desired
product (1.01 g, 63%) as a 9:1 mixture of trans:cis diastereomers.
LCMS M/Z (M+H) 339.
Step 3:
3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl-]-N-cyclopropyl--
4-methoxy-benzamide
##STR00193##
A mixture of
3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-4-methoxy-benz-
oic acid (42 mg, 0.125 mmol), cyclopropylamine (14 mg, 0.250 mmol),
triethylamine (0.053 mL, 0.38 mmol), and HATU (53 mg, 0.14 mmol) in
N,N-dimethylformamide (1 mL) was heated at 45.degree. C. overnight.
The reaction was filtered using ethyl acetate to rinse and the
filtrate was concentrated under reduced pressure. The residue was
purified by preparative HPLC (5-85% ACN/0.1% NH4OH in H2O) to yield
3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N-cyclopropyl--
4-methoxy-benzamide. (29.9 mg, 63%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 11.95 (s, 1H), 8.28 (d, J=4.2 Hz, 1H), 7.85
(dd, J=8.6, 2.4 Hz, 1H), 7.79 (d, J=2.3 Hz, 1H), 7.30-7.21 (m, 1H),
7.21-7.07 (m, 2H), 6.07-5.94 (m, 1H), 5.78-5.52 (m, 2H), 4.57 (dd,
J=4.7, 1.8 Hz, 2H), 3.77 (s, 3H), 2.89-2.70 (m, 1H), 1.72-1.59 (m,
2H), 0.75-0.61 (m, 2H), 0.61-0.50 (m, 2H). LCMS M/Z (M+H) 378.
The following compounds were prepared in a similar fashion to
Example 63
Examples 64-78
TABLE-US-00003 Example IUPAC Name NMR m/z 64 3-[6-[(E)-but-2-enyl]-
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.96 (s, 1H), 366
7-oxo-1H-pyrrolo[2,3- 7.43 (dd, J = 8.4, 2.2 Hz, 1H), 7.35 (d, J =
2.2 Hz, c]pyridin-4-yl]-4- 1H), 7.26 (t, J = 2.7 Hz, 1H),
methoxy-N,N- 7.20-7.08 (m, 2H), 6.04 (dd, J = 2.7, 1.8 Hz, 1H),
dimethyl-benzamide 5.78-5.54 (m, 2H), 4.56 (dd, J = 5.0, 1.6 Hz,
2H), 3.77 (s, 3H), 2.98 (s, 5H), 1.72-1.51 (m, 3H). 65
3-[6-[(E)-but-2-enyl]- .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
11.95 (s, 1H), 408 7-oxo-1H-pyrrolo[2,3- 8.38 (d, J = 6.5 Hz, 1H),
7.91 (dd, J = 8.6, 2.3 Hz, c]pyridin-4-yl]-4- 1H), 7.85 (d, J = 2.4
Hz, 1H), 7.26 (t, J = 2.8 Hz, methoxy-N- 1H), 7.21-7.13 (m, 1H),
7.12 (s, 1H), tetrahydrofuran-3-yl- 6.01 (dd, J = 2.8, 2.0 Hz, 1H),
5.81-5.53 (m, benzamide 2H), 4.57 (d, J = 5.3 Hz, 2H), 4.52-4.36
(m, 1H), 3.83 (td, J = 8.6, 6.7 Hz, 2H), 3.78 (s, 3H), 3.70 (td, J
= 8.0, 5.9 Hz, 1H), 3.56 (dd, J = 8.9, 4.4 Hz, 1H), 2.13 (dtd, J =
12.6, 7.9, 6.7 Hz, 1H), 1.97-1.83 (m, 1H), 1.72-1.61 (m, 3H). 66
3-[6-[(E)-but-2-enyl]- .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
11.96 (s, 1H), 364 7-oxo-1H-pyrrolo[2,3- 8.32 (t, J = 5.6 Hz, 1H),
7.87 (dd, J = 8.6, 2.4 Hz, c]pyridin-4-yl]-N- 1H), 7.81 (d, J = 2.3
Hz, 1H), 7.26 (t, J = 2.7 Hz, ethyl-4-methoxy- 1H), 7.16 (d, J =
8.7 Hz, 1H), 7.12 (s, benzamide 1H), 6.02 (dd, J = 2.8, 1.9 Hz,
1H), 5.84-5.50 (m, 2H), 4.57 (d, J = 5.3 Hz, 2H), 3.78 (s, 3H),
3.33-3.21 (m, 22H), 1.69-1.63 (m, 3H), 1.11 (t, J = 7.2 Hz, 3H). 67
3-[6-[(E)-but-2-enyl]- .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
11.96 (s, 1H), 352 7-oxo-1H-pyrrolo[2,3- 8.36-8.22 (m, 1H),
7.91-7.83 (m, 1H), c]pyridin-4-yl]-4- 7.81 (d, J = 2.3 Hz, 1H),
7.26 (t, J = 2.8 Hz, 1H), methoxy-N-methyl- 7.17 (d, J = 8.6 Hz,
1H), 7.15-7.08 (m, 1H), benzamide 6.03 (dd, J = 2.8, 2.0 Hz, 1H),
5.75-5.54 (m, 2H), 4.57 (d, J = 5.5 Hz, 2H), 3.78 (s, 3H), 2.76 (d,
J = 4.4 Hz, 3H), 1.74-1.61 (m, 3H). 68 6-[(E)-but-2-enyl]-4-
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.96 (s, 1H), 392
[2-methoxy-5- 7.60-7.51 (m, 1H), 7.46 (d, J = 2.2 Hz, 1H),
(pyrrolidine-1- 7.26 (dd, J = 3.2, 2.3 Hz, 1H), 7.17-7.09 (m,
carbonyl)phenyl]-1H- 2H), 6.04 (dd, J = 2.8, 1.9 Hz, 1H),
pyrrolo[2,3-c]pyridin- 5.75-5.52 (m, 2H), 4.62-4.50 (m, 2H), 3.76
(d, J = 8.0 Hz, 7-one 3H), 3.47 (s, 3H), 1.84 (d, J = 8.7 Hz, 4H),
1.72-1.61 (m, 3H). 69 3-[6-[(E)-but-2-enyl]- .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 11.97 (s, 1H), 402 7-oxo-1H-pyrrolo[2,3- 8.72
(t, J = 5.6 Hz, 1H), 7.98-7.90 (m, 1H), c]pyridin-4-yl]-N-(2,2-
7.86 (d, J = 2.4 Hz, 1H), 7.30-7.25 (m, 1H), difluoroethyl)-4-
7.25-7.17 (m, 1H), 7.13 (s, 1H), methoxy-benzamide 6.31-5.88 (m,
2H), 5.76-5.56 (m, 2H), 4.57 (d, J = 5.1 Hz, 2H), 3.78 (s, 3H),
3.73-3.57 (m, 3H), 1.71-1.59 (m, 3H). 70 3-[6-[(E)-but-2-enyl]-
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.96 (s, 1H), 394
7-oxo-1H-pyrrolo[2,3- 8.32 (t, J = 5.8 Hz, 1H), 7.88 (dd, J = 8.6,
2.3 Hz, c]pyridin-4-yl]-N- 1H), 7.82 (d, J = 2.3 Hz, 1H),
isobutyl-4-methoxy- 7.30-7.23 (m, 1H), 7.17 (d, J = 8.7 Hz, 1H),
7.13 (s, 1H), benzamide 6.02 (dd, J = 2.8, 2.0 Hz, 1H), 5.75-5.57
(m, 2H), 4.57 (d, J = 5.2 Hz, 2H), 3.78 (s, 3H), 3.14-3.00 (m, 2H),
1.94-1.73 (m, 1H), 1.73-1.57 (m, 3H), 0.88 (d, J = 6.7 Hz, 6H). 71
4-[5-(azetidine-1- .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
11.97 (s, 1H), 378 carbonyl)-2-methoxy- 7.64 (dd, J = 8.6, 2.3 Hz,
1H), 7.57 (d, J = 2.3 Hz, phenyl]-6-[(E)-but-2- 1H), 7.33-7.21 (m,
1H), 7.20-7.10 (m, enyl]-1H-pyrrolo[2,3- 2H), 6.05 (d, J = 2.7 Hz,
1H), 5.78-5.52 (m, c]pyridin-7-one 2H), 4.57 (d, J = 5.1 Hz, 2H),
4.34 (s, 2H), 4.04 (s, 2H), 2.32-2.20 (m, 2H), 1.71-1.59 (m, 3H).
72 3-[6-[(E)-but-2-enyl]- .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 11.96 (s, 1H), 409 7-oxo-1H-pyrrolo[2,3- 8.25 (t, J = 5.7
Hz, 1H), 7.87 (dd, J = 8.6, 2.3 Hz, c]pyridin-4-yl]-N-[2- 1H), 7.81
(d, J = 2.3 Hz, 1H), 7.26 (t, J = 2.7 Hz, (dimethylamino)ethyl]-
1H), 7.17 (d, J = 8.7 Hz, 1H), 7.12 (s, 4-methoxy-benzamide 1H),
6.01 (dd, J = 2.8, 1.9 Hz, 1H), 5.77-5.54 (m, 2H), 4.57 (d, J = 5.1
Hz, 2H), 3.78 (s, 3H), 3.40-3.24 (m, 2H), 2.43-2.33 (m, 2H), 2.16
(s, 6H), 1.71-1.57 (m, 3H). 73 3-[6-[(E)-but-2-enyl]- .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 11.96 (s, 1H), 382
7-oxo-1H-pyrrolo[2,3- 8.30 (t, J = 5.6 Hz, 1H), 7.89 (dd, J = 8.6,
2.3 Hz, c]pyridin-4-yl]-N-(2- 1H), 7.83 (d, J = 2.3 Hz, 1H),
hydroxyethyl)-4- 7.31-7.22 (m, 1H), 7.17 (d, J = 8.7 Hz, 1H), 7.12
(s, 1H), methoxy-benzamide 6.02 (dd, J = 2.8, 1.9 Hz, 1H),
5.81-5.53 (m, 2H), 4.75-4.63 (m, 1H), 4.57 (d, J = 5.2 Hz, 2H),
3.78 (s, 3H), 3.57-3.42 (m, 2H), 3.39-3.28 (m, 2H), 1.75-1.55 (m,
3H). 74 3-[6-[(E)-but-2-enyl]- .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 11.95 (s, 1H), 380 7-oxo-1H-pyrrolo[2,3- 8.39-8.25 (m, 1H),
7.91-7.83 (m, 1H), c]pyridin-4-yl]-4- 7.82 (d, J = 2.3 Hz, 1H),
7.26 (d, J = 2.8 Hz, 1H), methoxy-N-propyl- 7.21-7.09 (m, 2H), 6.02
(s, 1H), benzamide 5.82-5.54 (m, 2H), 4.64-4.52 (m, 2H), 3.76 (s,
4H), 3.19 (tt, J = 7.9, 2.7 Hz, 2H), 1.82-1.60 (m, 3H), 1.60-1.45
(m, 2H), 0.87 (t, J = 7.4, 2.7 Hz, 3H). 75 3-[6-[(E)-but-2-enyl]-
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.96 (s, 1H), 392
7-oxo-1H-pyrrolo[2,3- 8.46 (d, J = 7.6 Hz, 1H), 7.94-7.86 (m, 1H),
c]pyridin-4-yl]-N- 7.82 (d, J = 2.3 Hz, 1H), 7.31-7.22 (m, 1H),
cyclobutyl-4-methoxy- 7.17 (dd, J = 8.7, 3.6 Hz, 1H), 7.12 (d, J =
3.1 Hz, benzamide 1H), 6.01 (dd, J = 2.8, 1.9 Hz, 1H), 5.78-5.50
(m, 2H), 4.57 (d, J = 5.3 Hz, 2H), 4.50-4.31 (m, 1H), 3.78 (s, 3H),
2.28-2.13 (m, 2H), 2.13-1.95 (m, 2H), 1.82-1.48 (m, 5H). 76
3-[6-[(E)-but-2-enyl]- .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
11.96 (s, 1H), 392 7-oxo-1H-pyrrolo[2,3- 8.42 (t, J = 5.7 Hz, 1H),
7.89 (dd, J = 8.6, 2.3 Hz, c]pyridin-4-yl]-N- 1H), 7.83 (d, J = 2.4
Hz, 1H), (cyclopropylmethyl)-4- 7.32-7.22 (m, 1H), 7.17 (d, J = 8.6
Hz, 1H), 7.13 (s, 1H), methoxy-benzamide 6.01 (dd, J = 2.8, 1.9 Hz,
1H), 5.82-5.59 (m, 2H), 4.68-4.54 (m, 2H), 3.78 (s, 3H), 3.13 (dd,
J = 6.7, 5.7 Hz, 2H), 1.76-1.57 (m, 2H), 1.10-0.93 (m, 1H),
0.51-0.33 (m, 2H), 0.29-0.14 (m, 2H). 77 4-[5-(6-acetyl-2,6- 1H NMR
(400 MHz, DMSO) .delta. 11.97 (s, 1H), 461 diazaspiro[3.3]heptane-
7.65 (dd, J = 8.6, 2.3 Hz, 1H), 7.56 (d, J = 2.2 Hz, 2-carbonyl)-2-
1H), 7.27 (t, J = 2.8 Hz, 1H), methoxy-phenyl]-6- 7.24-7.14 (m,
1H), 7.13 (d, J = 9.6 Hz, 1H), [(E)-but-2-enyl]-1H- 6.10-6.01 (m,
1H), 5.77-5.55 (m, 2H), 4.57 (d, J = 4.4 Hz, pyrrolo[2,3-c]pyridin-
2H), 4.57-4.44 (m, 2H), 4.25 (s, 2H), 7-one 4.18 (s, 2H), 3.98 (s,
2H), 3.79 (s, 3H), 1.72 (s, 3H), 1.66 (d, J = 5.0 Hz, 3H). 78
4-[5-(6-acetyl-2,6- 1H NMR (400 MHz, DMSO) .delta. 11.93 (s, 1H),
463 diazaspiro[3.3]heptane- 7.65 (dd, J = 8.6, 2.3 Hz, 1H), 7.58
(d, J = 2.2 Hz, 2-carbonyl)-2- 1H), 7.26 (t, J = 2.7 Hz, 1H), 7.17
(t, J = 4.3 Hz, methoxy-phenyl]-6- 2H), 6.09-6.01 (m, 1H), 4.49 (s,
2H), butyl-1H-pyrrolo[2,3- 4.26 (s, 2H), 4.18 (s, 2H), 4.05-3.95
(m, 4H), c]pyridin-7-one 3.79 (s, 3H), 2.53-2.47 (m, 3H), 1.72 (s,
2H), 1.71-1.65 (m, 2H), 1.39-1.28 (m, 2H), 0.97-0.88 (m, 3H).
Example 79
6-[(E)-but-2-enyl]-4-[4-(1-hydroxy-1-methyl-ethyl)-2-methoxy-phenyl]-1H-py-
rrolo[2,3-e]pyridin-7-one
##STR00194## Step 1:
4-bromo-6-[(E)-but-2-enyl]-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridin-7-one
##STR00195##
Title compound was prepared in the same manner as described in
Example 1, Step 1.
Step 2:
methyl
4-[6-[(E)-but-2-enyl]-7-oxo-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridi-
n-4-yl]-3-methoxy-benzoate
##STR00196##
Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)
(141 mg, 0.2 mmol) was added to a mixture of
4-bromo-6-[(E)-but-2-enyl]-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridin-7-one
(Step 1, 1.52 g, 3.6 mmol) and methyl
3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate
(1.56 g, 5.3 mmol) in 1,4-dioxane (10 mL) and 2 M potassium
phosphate tribasic in water (3 equiv., 10.7 mmol). The reaction was
heated to 90.degree. C. for 2 h. The reaction was cooled to room
temperature, diluted with ethyl acetate, and washed with water. The
organic solution was dried over sodium sulfate and concentrated
under reduced pressure. The residue was purified by silica gel
chromatography (10-35% ethyl acetate: heptanes) to yield title
compound (470 mg, 26%). LCMS M/Z (M+H) 507.
Step 3:
6-[(E)-but-2-enyl]-4-[4-(1-hydroxy-1-methyl-ethyl)-2-methoxy-phenyl]-1H-py-
rrolo[2,3-c]pyridin-7-one
##STR00197##
Methyl magnesium bromide, (3.0 M in diethyl ether, 0.47 mL, 1.4
mmol) was added dropwise to a cooled (0.degree. C.) solution of
methyl
4-[6-[(E)-but-2-enyl]-7-oxo-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridin-4-yl-
]-3-methoxy-benzoate (233 mg, 0.46 mmol) in tetrahydrofuran (8 mL).
The reaction was allowed to gradually warm to room temperature and
then quenched with 1 N HCl until the solution was pH 3. The mixture
was diluted with water (100 mL) and then extracted with ethyl
acetate (3.times.50 mL). The combined organic extracts were dried
over sodium sulfate and concentrated under reduced pressure. The
residue was taken up in methanol (1 mL) and 10 M potassium
hydroxide in water (0.25 mL) was added. The reaction was heated to
45.degree. C. for 2 h and then concentrated under reduced pressure.
The residue was taken up in water (50 mL) and extracted with
dichloromethane (3.times.30 mL). The combined organic extracts were
dried over sodium sulfate and concentrated under reduced pressure.
The residue was purified by preparative HPLC 50% ACN/0.1% NH4OH in
H2O) yielding
6-[(E)-but-2-enyl]-4-[4-(1-hydroxy-1-methyl-ethyl)-2-methoxy-phenyl]-1H-p-
yrrolo[2,3-c]pyridin-7-one (104 mg, 64%). .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 11.91 (s, 1H), 7.29-7.14 (m, 3H), 7.10-7.02 (m,
2H), 6.12-5.98 (m, 1H), 5.77-5.53 (m, 2H), 5.03 (s, 1H), 4.55 (d,
J=5.4 Hz, 2H), 3.73 (s, 3H), 1.72-1.61 (m, 2H), 1.47 (s, 5H). LCMS
M/Z (M+H) 353.
The following compounds were prepared in a similar fashion to
Example 79:
Examples 80-81
TABLE-US-00004 Example IUPAC Name NMR m/z 80 6-butyl-4-[4-(1- 1H
NMR (400 MHz, DMSO) .delta. 11.88 (s, 1H), 355 hydroxy-1-methyl-
7.27-7.17 (m, 3H), 7.11 (s, 1H), 7.07 (dd, J = 7.8,
ethyl)-2-methoxy- 1.7 Hz, 1H), 6.08-6.02 (m, 1H), 5.04 (s,
phenyl]-1H- 1H), 3.99 (t, J = 7.2 Hz, 2H), 3.73 (s, 3H),
pyrrolo[2,3-c]pyridin- 1.73-1.61 (m, 2H), 1.48 (s, 6H), 1.39-1.26
(m, 2H), 7-one 0.92 (t, J = 7.4 Hz, 3H). 81 6-[(E)-but-2-enyl]-4-
1H NMR (400 MHz, DMSO) .delta. 12.09 (s, 1H), 323 [4-(1-hydroxy-1-
7.61-7.42 (m, 4H), 7.34 (s, 1H), 7.23 (d, J = 3.5 Hz,
methyl-ethyl)phenyl]- 1H), 6.44 (d, J = 2.5 Hz, 1H),
1H-pyrrolo[2,3- 5.75-5.53 (m, 2H), 5.00 (d, J = 4.1 Hz, 1H), 4.71
(d, J = 6.5 Hz, c]pyridin-7-one 1H), 4.59 (d, J = 4.8 Hz, 2H), 1.79
(d, J = 6.8 Hz, 1H), 1.74-1.58 (m, 3H), 1.46 (d, J = 4.1 Hz,
6H).
Example 82
6-butyl-4-(4-(2-hydroxypropan-2-yl)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)--
one
##STR00198## Step 1:
2-(4-bromophenyl)propan-2-ol
##STR00199##
n-Butyl lithium (2.5 M in hexanes, 6.8 mL, 17.0 mmol) was added
dropwise to a stirred and cooled (-78.degree. C.) solution of
1,4-dibromobenzene (4.0 g, 16.9 mmol) in THF (50 mL). After
addition, stirring at -78.degree. C. was continued for 1 h, and
acetone (3.0 g, 51.7 mmol) was added dropwise. The resulting
mixture was warmed to 0.degree. C. and stirred for another 3 h
before being quenched by addition of saturated aqueous ammonium
chloride (40 mL). The mixture was extracted with 75% ethyl
acetate/petroleum ether (3.times.50 mL). The combined organic
extracts were washed with brine (50 mL), dried over sodium sulfate
and concentrated under reduced pressure to give title compound (1.8
g, 50%) as a colorless oil. LCMS M/Z [M-OH.sup.+] 197.
Step 2:
2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-0)phenyl)propan-2-ol
##STR00200##
A mixture of potassium acetate (1.4 g, 13.9 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.2 g,
8.4 mmol), 2-(4-bromophenyl)propan-2-ol (1.5 g, 7.0 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]palladium(ii) dichloride
(0.15 g, 0.2 mmol) in dioxane (15 mL) was degassed for 30 min and
then heated at 80.degree. C. for 12 h under nitrogen. After
cooling, the reaction mixture was filtered through a pad of Celite
using ethyl acetate to rinse. The filtrate was evaporated and the
residue was purified by silica gel chromatography (petroleum
ether:ethyl acetate 1:1) to give the title compound (1.1 g, 69%) as
a colorless oil.
Step 3:
4-bromo-6-butyl-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridin-7-one
##STR00201##
Title compound was prepared in the same manner as described in
Example 1, Step 1.
Step 4:
4-bromo-6-butyl-1H-pyrrolo[2,3-c]pyridin-7-one
##STR00202##
Sodium hydroxide (0.5 g, 12.5 mmol) in water (2 mL) was added
slowly to a solution of
4-bromo-6-butyl-1H-pyrrolo[2,3-c]pyridin-7-one (1.0 g, 2.4 mmol) in
methanol (20 mL) and water (2 mL). The resulting mixture was heated
at 80.degree. C. for 2 h. After cooling, the mixture was
concentrated under reduced pressure and the aqueous residue was
diluted with water (30 mL). The resulting precipitated was
collected by filtration, washed with water (2.times.30 mL) and
concentrated under reduced pressure to give the title compound (0.5
g, 78%) as a white solid. LCMS M/Z (M+1) 270.
Step 5:
6-butyl-4-(4-(2-hydroxypropan-2-yl)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)--
one
##STR00203##
A mixture of 4-bromo-6-butyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
(190 mg, 0.7 mmol),
2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol
(210 mg, 0.8 mmol), cesium carbonate (456 mg, 1.4 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]palladium(ii) dichloride (51
mg, 0.07 mmol) in dioxane (5 mL) and water (1 mL) was heated at
90.degree. C. for 3 h under nitrogen protection. After cooling, the
mixture was filtered through a small pad of Celite using ethyl
acetate to rinse. The filtrate was concentrated under reduced
pressure and the residue was purified by preparative HPLC,
acetonitrile:water (10 nM ammonia bicarbonate), 55%-85%, to give
the title compound (38 mg, 17%) as a white solid. .sup.1HNMR (400
MHz, DMSO-d6): .delta. 12.07 (s, 1H), 7.55-7.50 (m, 4H), 7.34-7.33
(t, 0.1=2.6 Hz, 1H), 7.30 (s, 1H), 6.44 (t, J=2.2 Hz, 1H), 5.01 (d,
J=3.6 Hz, 1H), 4.02 (t, J=7.2 Hz, 2H), 1.70-1.66 (m, 2H), 1.46 (s,
6H), 1.35-1.30 (m, 2H), 0.93-0.90 (t, J=7.2, 3H). LCMS M/Z (M+H)
329.
Example 83 was Prepared in a Similar Fashion to Example 82
TABLE-US-00005 Example IUPAC Name NMR m/z 83
6-(2-cyclopropylethyl)- 1H NMR (400 MHz, DMSO-d6): .delta. 12.05
(s, 1 336 4-[4-(1-hydroxy-1- H), 7.55-7.50 (m, 4 H), 7.34-7.32 (m,
2 H), methyl-ethyl)phenyl]- 6.44-6.42 (m, 1 H), 5.02 (s, 1 H),
4.12-4.07 (m, 1H-pyrrolo[2,3- 2 H), 1.62-1.57 (m, 2 H), 1.41 (s, 6
H), c]pyridin-7-one 0.73-0.68 (m, 1 H), 0.41-0.39 (m, 2 H),
0.09-0.05 (m, 2H).
Example 84
7-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-4-methyl-1,3,4,-
5-tetrahydro-1,5-benzodiazepin-2-one
##STR00204## Step 1:
3-(5-bromo-2-nitro-anilino)butanoic acid
##STR00205##
A round bottomed flask was charged with
4-bromo-2-fluoro-1-nitrobenzene (0.511 g, 2.321 mmol),
(R)-3-aminobutanoic acid, HCl (0.216 g, 1.548 mmol), potassium
carbonate (0.428 g, 3.10 mmol) and DMSO (7.5 mL). The flask was
heated to 100.degree. C. and stirred 18 h. After cooling, the
mixture was poured into 1 M HCl and washed with ethyl acetate
(3.times.). The combined organic layers were washed with brine and
concentrated under reduced pressure. The crude was purified by
silica gel chromatography (eluting with dichloromethane/methanol)
to yield 3-((5-bromo-2-nitrophenyl)amino)butanoic acid, which was
used in the subsequent reduction. LCMS M/Z (M+H) 303/305.
Step 2:
7-bromo-4-methyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2-one
##STR00206##
A disposable reaction tube was charged with
(R)-3-(5-bromo-2-nitrophenylamino)butanoic acid (0.283 g, 0.934
mmol), ethanol (6 mL) and acetic acid (1.069 ml, 18.67 mmol). Iron
(0.417 g, 7.47 mmol) was added, and the suspension was stirred at
110.degree. C. 18 h. After cooling, the mixture was filtered
through celite and concentrated under reduced pressure to a residue
that was purified by silica gel chromatography (eluting with
hexanes/ethyl acetate) to yield the title compound. LCMS M/Z (M+H)
255/257.
Step 3:
4-bromo-6-[(E)-but-2-enyl]-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridin-7-one
##STR00207##
A disposable tube was charged with
4-bromo-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (Intermediate A)
(500 mg, 1.362 mmol), (E)-1-chlorobut-2-ene (265 .mu.l, 2.72 mmol),
cesium carbonate (665 mg, 2.042 mmol), and 1,4-dioxane (10 mL), and
the mixture was stirred at room temperature overnight. The reaction
was quenched with water, and the product was extracted three times
with ethyl acetate before the organic layers were combined, dried
with sodium sulfate and concentrated under reduced pressure to
yield
(E)-4-bromo-6-(but-2-en-1-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one,
which was used without purification in the subsequent step.
Step 4:
6-[(E)-but-2-enyl]-1-(p-tolylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxab-
orolan-2-yl)pyrrolo[2,3-c]pyridin-7-one
##STR00208##
A disposable reaction vial was charged with
(E)-4-bromo-6-(but-2-enyl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
(150 mg, 0.36 mmol), triethylamine (149 .mu.l, 1.068 mmol),
bis(acetonitrile)dichloropalladium(II) (9.2 mg, 0.036 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (14.6 mg, 0.036
mmol), and 1,4-dioxane (2 mL).
4,4,5,5-tetramethyl-1,3,2-dioxaborolane (103 pa, 0.712 mmol) was
added, and the mixture was stirred at room temperature while gas
was evolved from the reaction. After 15 min, the mixture was heated
to 100.degree. C. and stirred 2 h before being cooled, diluted with
ethyl acetate, stripped with 1,4-dioxane twice, and concentrated to
yield
(E)-6-(but-2-en-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y-
l)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one as a yellow oil that
was used without purification in the next step.
Step 5:
7-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-4-methyl-1,3,4,-
5-tetrahydro-1,5-benzodiazepin-7-one
##STR00209##
A disposable reaction tube was charged with
(E)-6-(but-2-enyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosy-
l-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (167 mg, 0.357 mmol),
7-bromo-4-methyl-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (76
mg, 0.297 mmol), tetrakis(triphenylphosphine)palladium(O) (34.3 mg,
0.030 mmol), potassium phosphate (82 mg, 0.594 mmol). 1,4-dioxane
(3.8 mL)/water (0.2 mL) was added, and the mixture was degassed
before being stirred at 100.degree. C. 2 h. The reaction was
cooled, quenched with 2 M sodium hydroxide and methanol, and
stirred at room temperature 2 h. Ammonium hydroxide (sat., aq.) was
added, and the product was extracted 4.times. with ethyl acetate.
The organic layers were combined and concentrated under reduced
pressure to yield a residue that was purified by silica gel
chromatography (eluting with Hexanes and ethyl acetate) to provide
the title compound as a white amorphous solid (31 mg). .sup.1H NMR
(400 MHz, DMSO-d6) =12.10 (br. s., 1H), 9.51 (s, 1H), 7.35 (t,
J=2.7 Hz, 1H), 7.17 (s, 1H), 7.11 (s, 1H), 6.92 (dd, J=8.0, 13.0
Hz, 2H), 6.47 (t, J=2.4 Hz, 1H), 5.67-5.62 (m, 2H), 5.48 (br. s.,
1H), 4.58 (d, J=3.5 Hz, 2H), 3.92-3.78 (m, 1H), 2.47 (d, J=3.7 Hz,
1H), 2.27 (dd, J=7.5, 13.5 Hz, 1H), 1.65 (d, J=4.4 Hz, 3H), 1.21
(d, J=6.2 Hz, 3H). LCMS M/Z (M+H) 363.
Example 85
3-(6-(2-cyclopropylethyl)-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyri-
din-4-yl)-N,N-dimethylbenzamide
##STR00210## Step 1:
4-bromo-6-(2-cyclopropylethyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
##STR00211##
Sodium hydride (60% oil dispersion, 70.5 mg, 1.76 mmol) was added
to cooled (0.degree. C.) solution of
4-bromo-2-methyl-1,6-dihydropyrrolo[2,3-c]pyridin-7-one
(Intermediate B) (400 mg, 1.76 mmol) in THF (7 mL). After addition,
the reaction mixture was stirred for 0.5 h, and then a solution of
(2-iodoethyl) cyclopropane (345 mg, 1.76 mmol) in THF (1 mL) was
added. The mixture was warmed to room temperature and stirred for 2
h, at which time LCMS indicated that the reaction had gone to
completion. The reaction was quenched by the addition of saturated
aqueous ammonium chloride (0.5 mL), and then concentrated under
reduced pressure. The residue was dissolved in ethyl acetate (50
mL), washed with water (2.times.15 mL), and concentrated under
reduced pressure. The residue was purified by silica gel
chromatography (petroleum ether:ethyl acetate 1:1) to give the
title compound (150 mg, 29% yield) as a light brown solid. .sup.1H
NMR (400 MHz, CD.sub.3OD): .delta. 7.35 (s, 1H), 6.08 (s, 1H),
4.15-4.04 (m, 2H), 2.54-2.24 (m, 3H), 1.70-1.54 (m, 2H), 0.77-0.60
(m, 1H), 0.48-0.35 (m, 2H), 0.08-0.04 (m, 2H). LCMS M/Z (M+H)
295.
Step 2:
3-(6-(2-cyclopropylethyl)-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyri-
din-4-yl)-N,N-dimethylbenzamide
##STR00212##
A mixture of 4-bromo-2-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
(79 mg, 0.27 mmol), (3-(dimethylcarbamoyl)phenyl)boronic acid (51.7
mg, 0.27 mmol), cesium carbonate (174 mg, 0.54 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]palladium(ii) dichloride (10
mg, 0.01 mmol) in dioxane (3 mL) and water (0.5 mL) was subjected
to microwave irradiation at 110.degree. C. for 0.5 h. After
cooling, the mixture was filtered through a small pad of Celite
using ethyl acetate to rinse. The filtrate was concentrated under
reduced pressure and the residue was purified by preparative HPLC,
acetonitrile:water (0.3% formic acid), 46%-76%, to give the title
compound (30.5 mg, 31%) as a white solid. .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. 7.72 (d, J=8.0 Hz, 1H), 7.65 (s, 1H), 7.57 (t,
J=7.4 Hz, 1H), 7.42 (d, J=7.6 Hz, 1H), 7.33 (s, 1H), 6.28 (s, 1H),
4.23 (t, J=7.0 Hz, 2H), 3.15 (s, 3H), 3.09 (s, 3H), 2.45 (s, 3H),
1.75-1.69 (m, 2H), 0.79-0.77 (m, 1H), 0.48-0.43 (m, 2H), 0.09-0.05
(m, 2H). LCMS M/Z (M+H) 364.
The following compounds were prepared in a similar fashion to
Example 85:
Examples 86-103
TABLE-US-00006 Example IUPAC Name NMR m/z 86 3-(6-butyl-2-methyl-7-
1H NMR (400 MHz, CD3OD): .delta. 7.70 (d, J = 7.6 Hz, 352
oxo-1H-pyrrolo[2,3- 1 H), 7.62 (s, 1 H), 7.53-7.57 (m, 1 H),
c]pyridin-4-yl)-N,N- 7.40 (d, J = 7.2 Hz, 1 H), 7.27 (s, 1 H), 6.26
(s, dimethyl-benzamide 1 H), 4.12 (t, J = 7.4 Hz, 2 H), 3.13 (s, 3
H), 3.07 (s, 3 H), 2.43 (s, 3 H), 1.83-1.75 (m, 2 H), 1.47-1.38 (m,
2 H), 0.97 (t, J = 7.4 Hz, 3 H). 87 3-(6-butyl-2-methyl-7- .sup.1H
NMR (400 MHz, CD.sub.3OD): .delta. 7.50-7.45 (m, 382
oxo-1H-pyrrolo[2,3- 2 H), 7.19-7.17 (t, J = 4.4 Hz, 1 H), 5.94 (s,
1 c]pyridin-4-yl)-4- H), 4.11 (t, J = 7.4 Hz, 2 H), 3.86 (s, 3 H),
methoxy-N,N- 3.12 (s, 6 H), 2.41 (s, 3 H), 1.83-1.76 (m, 2 H),
dimethyl-benzamide 1.49-1.40 (m, 2 H), 1.01 (t, J = 7.2 Hz, 3 H).
88 3-[6-(2- .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 7.52 7.47
(m, 394 cyclopropylethyl)-2- 2 H), 7.28 (s, 1 H), 7.19 (d, J = 8.4
Hz, 1 H), methyl-7-oxo-1H- 4.24 (t, J = 7.0 Hz, 2 H), 3.85 (s, 3
H), 3.13 (s, pyrrolo[2,3-c]pyridin- 6 H), 2.43 (s, 3 H), 1.72 (m, 2
H), 4-yl]-4-methoxy-N,N- 0.77-0.74 (m, 1 H), 0.48-0.44 (m, 2 H),
0.09-0.05 (m, 2 dimethyl-benzamide H). 89 6-but-3-enyl-4-[4- 1H NMR
(400 MHz, DMSO-d6) .delta. 11.92 (s, 426 chloro-3-(morpholine- 1H),
7.65 (dd, J = 8.5, 2.2 Hz, 1H), 4-carbonyl)phenyl]-2- 7.62-7.51 (m,
2H), 7.42 (s, 1H), 6.15 (dd. J = 1.9, 1.0 Hz,
methyl-1H-pyrrolo[2,3- 1H), 5.85 (ddt, J = 17.0, 10.2, 6.7 Hz, 1H),
c]pyridin-7-one 5.19-4.96 (m, 2H), 4.09 (t, J = 7.3 Hz, 2H),
3.82-3.50 (m, 6H), 3.21 (m, J = 5.1 Hz, 2H), 2.47 (m, J = 6.6 Hz,
2H), 2.34 (s, 3H). 90 6-[(E)-but-2-enyl]-2- 1H NMR (400 MHz,
DMSO-d6) .delta. 11.91 (s, 391 methyl-4-[4- 1H), 7.67-7.56 (m, 2H),
7.55-7.41 (m, 2H), (morpholine-4- 7.30 (d, J = 2.8 Hz, 1H),
6.25-6.14 (m, 1H), carbonyl)phenyl]-1H- 5.71-5.49 (m, 2H), 4.70 (d,
J = 6.7 Hz, 1H), pyrrolo[2,3-c]pyridin- 4.64-4.50 (m, 2H), 3.57 (d,
J = 38.6 Hz, 7H), 7-one 2.34 (d, J = 0.8 Hz, 3H), 1.82-1.73 (m,
1H), 1.69-1.58 (m, 2H). 91 6-[(E)-but-2-enyl]-2- 1H NMR (400 MHz,
DMSO-d6) .delta. 11.91 (s, 376 methyl-4-[4- 1H), 7.65-7.55 (m, 4H),
7.31 (d, J = 2.9 Hz, (pyrrolidine-1- 1H), 6.21 (dd, J = 2.0, 1.0
Hz, 1H), carbonyl)phenyl]-1H- 5.71-5.60 (m, 2H), 4.59 (d, J = 4.1
Hz, 2H), 3.47 (dt, J = 13.8, pyrrolo[2,3-c]pyridin- 6.4 Hz, 4H),
3.37-3.24 (m, 19H), 7-one 2.34 (d, J = 0.8 Hz, 3H), 1.93-1.75 (m,
5H), 1.68-1.61 (m, 2H). 92 6-[(E)-but-2-enyl]-4-[3- 1H NMR (400
MHz, DMSO-d6) .delta. 11.95 (s, 410 chloro-4-(pyrrolidine-1- 1H),
7.69-7.57 (m, 2H), 7.48-7.37 (m, 2H), carbonyl)phenyl]-2- 6.20 (dd,
J = 2.0, 1.1 Hz, 1H), 5.72-5.57 (m, methyl-1H-pyrrolo[2,3- 2H),
4.58 (d, J = 4.1 Hz, 2H), 3.49 (t, J = 6.7 Hz, c]pyridin-7-one 2H),
3.16 (t, J = 6.5 Hz, 2H), 2.35 (d, J = 0.8 Hz, 3H), 1.96-1.75 (m,
5H), 1.68-1.61 (m, 2H). 93 6-[(E)-but-2-enyl]-4- 1H NMR (400 MHz,
DMSO-d6) .delta. 11.93 (s, 428 [2,3-difluoro-4- 1H), 7.44-7.35 (m,
1H), 7.34-7.25 (m, 2H), (morpholine-4- 6.00 (s, 1H), 5.70-5.60 (m,
2H), carbonyl)phenyl]-2- 4.60-4.54 (m, 2H), 3.67 (s, 4H), 3.60-3.53
(m, 2H), methyl-1H-pyrrolo[2,3- 3.32-3.25 (m, 4H), 2.32 (d, J = 0.8
Hz, 3H), c]pyridin-7-one 1.65 (dt, J = 5.0, 1.1 Hz, 2H). 94
6-[(E)-but-2-enyl]-4-[3- 1H NMR (400 MHz, DMSO-d6) .delta. 11.89
(s, 422 methoxy-4- 1H), 7.35-7.22 (m, 2H), 7.22-7.14 (m, 2H),
(morpholine-4- 6.25 (dd, J = 2.1, 1.1 Hz, 1H), 5.69-5.61 (m,
carbonyl)phenyl]-2- 2H), 4.58 (dd, J = 4.1, 2.1 Hz, 2H), 3.88 (s,
methyl-1H-pyrrolo[2,3- 3H), 3.66-3.61 (m, 4H), 3.57-3.46 (m, 2H),
c]pyridin-7-one 3.21-3.16 (m, 2H), 2.34 (s, 3H), 1.68-1.61 (m, 2H).
95 6-[(E)-but-2-enyl]-4-[3- 1H NMR (400 MHz, DMSO-d6) .delta. 11.95
(s, 425 chloro-4-(morpholine- 1H), 7.67 (d, J = 1.7 Hz, 1H), 7.62
(dd, J = 7.9, 4-carbonyl)phenyl]-2- 1.7 Hz, 1H), 7.45 (d, J = 7.9
Hz, 1H), 7.39 (d, J = 4.0 Hz, methyl-1H-pyrrolo[2,3- 1H), 6.21 (d,
J = 1.7 Hz, 1H), c]pyridin-7-one 5.75-5.51 (m, 2H), 4.62-4.46 (m,
2H), 3.74-3.61 (m, 4H), 3.60-3.54 (m, 2H), 3.23-3.17 (m, 2H), 2.34
(s, 3H), 1.67-1.62 (m, 2H). 96 6-but-3-enyl-4-[3- 1H NMR (400 MHz,
DMSO-d6) .delta. 11.93 (s, 396 fluoro-5-(morpholine- 1H), 7.56-7.38
(m, 3H), 7.21 (ddd, J = 8.8, 4-carbonyl)phenyl]-2- 2.5, 1.3 Hz,
1H), 6.18 (dd, J = 2.0, 1.0 Hz, 1H), methyl-1H-pyrrolo[2,3- 5.85
(m, J = 17.0, 10.2, 6.7 Hz, 1H), c]pyridin-7-one 5.16-4.96 (m, 2H),
4.09 (t, J = 7.3 Hz, 2H), 3.62 (m, 8H), 2.47 (m, J = 1.3 Hz, 2H),
2.35 (s, 3H). 97 6-but-3-enyl-4-[4- 1H NMR (400 MHz, DMSO-d6)
.delta. 11.90 (s, 410 fluoro-3-(morpholine- 1H), 7.68 (m, J = 8.6,
5.1, 2.4 Hz, 1H), 4-carbonyl)phenyl]-2- 7.56 (dd, J = 6.4, 2.4 Hz,
1H), 7.42-7.33 (m, 2H), methyl-1H-pyrrolo[2,3- 6.13 (dd, J = 2.1,
1.0 Hz, 1H), 5.94-5.79 (m, c]pyridin-7-one 1H), 5.14-4.97 (m, 2H),
4.09 (t, J = 7.3 Hz, 2H), 3.67 (m, 4H), 3.57 (m, 2H), 2.47 (m, J =
6.7 Hz, 2H), 2.34 (s, 3H). 98 6-[(E)-but-2-enyl]-4-[5- .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 8.80 (d, J = 1.8 Hz, 427
chloro-6-(morpholine- 1 H), 8.23 (d, J = 1.8 Hz, 1 H), 7.44 (s, 1
4-carbonyl)-3-pyridyl]- H), 6.31 (s, 1 H), 5.85-5.57 (m, 2 H), 4.84
(d, J = 7.0 Hz, 2-methyl-1H- 0.55 H), 4.70 (d, J = 5.5 Hz, 1.45 H),
pyrrolo[2,3-c]pyridin- 3.90-3.78 (m, 4 H), 3.73-3.66 (m, 2 H), 2.47
(s, 7-one 3 H), 1.86 (d, J = 5.3 Hz, 0.56 H), 1.73 (dd, J = 0.9,
6.1 Hz, 2.4 H). 99 6-[(E)-but-2-enyl]-4-[3- .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 7.69 (d, J = 1.2 Hz, 439 chloro-4-(4- 1 H),
7.65-7.63 (m, 1 H), 7.44 (d, J = 8.0 Hz, methylpiperazine-1- 1 H),
7.27 (s, 1 H), 6.26 (s, 1 H), carbonyl)phenyl]-2- 5.78-5.64 (m, 2
H), 4.67 (d, J = 6.0 Hz, 2 H), methyl-1H-pyrrolo[2,3- 3.84-3.82 (m,
2 H), 3.38-3.34 (m, 2 H), 2.57-2.55 (m, 2 c]pyridin-7-one H),
2.49-2.47 (m, 1 H), 2.44 (s, 3 H), 2.34 (s, 3 H), 1.71 (d, J = 6.0
Hz, 3 H). 100 6-[(E)-but-2-enyl]-2- .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 12.00 (s, 1 H), 406 methyl-4-[3-methyl-4- 7.42
(d, J = 5.1 Hz, 2 H), 7.25 (d, J = 8.3 Hz, 1 (morpholine-4- H),
6.93-7.02 (m, 1 H), 6.22 (s, 1 H), carbonyl)phenyl]-1H- 5.67-5.74
(m, 1 H), 4.71 (d, J = 2.9 Hz, 2 H), pyrrolo[2,3-c]pyridin-
3.78-3.91 (m, 4 H), 3.63 (s, 2 H), 3.35 (s, 2 H), 2.49 (s, 3 7-one
H), 2.40 (s, 3 H), 1.84 (d, J = 6.9 Hz, 1 H), 1.72 (d, J = 4.4 Hz,
2 H). 101 6-allyl-4-[3-chloro-4- .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 12.03 (br. s, 1 412 (morpholine-4- H), 7.67
(s, 1 H), 7.63 (dd, J = 1.4, 7.8 Hz, 1 carbonyl)phenyl]-2- H), 7.46
(d, J = 7.9 Hz, 1 H), 7.41 (s, 1 H), methyl-1H-pyrrolo[2,3- 6.23
(s, 1 H), 6.09-5.93 (m, 1 H), 5.20-5.04 (m, 2 c]pyridin-7-one H),
4.66 (d, J = 5.1 Hz, 2 H), 3.73-3.61 (m, 4 H), 3.59-3.53 (m, 2 H),
3.20 (d, J = 4.6 Hz, 2 H), 2.35 (s, 3 H). 102 6-allyl-4-[2,5-
.sup.1H NMR (400 MHz, CDCl.sub.3) d 10.49 (br. s, 1H), 438
dimethoxy-4- 7.03 (s, 1 H), 6.98 (s, 1 H), 6.94 (s, 1 H),
(morpholine-4- 5.94-6.09 (m, 2 H), 5.17-5.27 (m, 2 H), 4.75 (d, J =
5.3 Hz, carbonyl)phenyl]-2- 2 H), 3.73-3.86 (m, 10 H), 3.70 (br. s,
1 methyl-1H-pyrrolo[2,3- H), 3.65 (br. s, 1 H), 3.41 (br. s, 1 H),
2.45 (s, 3 c]pyridin-7-one H). 103 6-[(E)-but-2-enyl]-4-[3- .sup.1H
NMR (4:1 E/Z mixture) (400 MHz, DMSO- 423 methoxy-5- d6) d 11.77
(br. s., 1H), 8.26 (d, J = 1.22 Hz, (morpholine-4- 1H), 7.63 (s,
1H), 7.54 (d, J = 1.46 Hz, 1H), carbonyl)-2-pyridyl]-2- 6.24-6.26
(m, 1H), 5.65 (dd, J = 5.13, 7.32 Hz, methyl-1H-pyrrolo[2,3- 2H),
4.58 (d, J = 4.64 Hz, 2H), c]pyridin-7-one 3.82-3.90 (m, 3H),
3.40-3.76 (m, 8H), 2.31 (s, 3H), 1.67 (d, J = 5.37 Hz, 3H).
Example 104
6-[(E)-but-2-enyl]-4-[4-chloro-5-(morpholine-4-carbonyl)-2-pyridyl]-2-meth-
yl-1H-pyrrolo[2,3-c]pyridin-7-one
##STR00213## Step 1:
(E)-6-(but-2-en-1-yl)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
-yl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
##STR00214##
To a mixture of
4-bromo-6-[(E)-but-2-enyl]-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-one
(3.00 g, 10.7 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(6.83 g, 53.3 mmol) in 1,4-dioxane (50 mL) was added triethylamine
(3.24 g, 32.01 mmol), SPhos (2.19 g, 5.34 mmol) and
bis(acetonitrile)dichloropalladium(II) (277.0 mg, 1.07 mmol). The
reaction was then stirred at 80.degree. C. for 16 hrs under N.sub.2
atmosphere. The mixture was then concentrated under reduced
pressure, and the residue then purified by silica gel
chromatography (Petroleum ether/ethyl acetate=5/1) to give
6-[(E)-but-2-enyl]-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y-
l)-1H-pyrrolo[2,3-c]pyridin-7-one (4.00 g, crude) as a yellow
solid.
Step 2:
(E)-ethyl
6-(6-(but-2-en-1-yl)-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c-
]pyridin-4-yl)-4-chloronicotinate
##STR00215##
This compound was prepared in a similar procedure to Example 62,
step 3.
Step 3:
(E)-6-(6-(but-2-en-1-yl)-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyrid-
in-4-yl)-4-chloronicotinic acid
##STR00216##
This compound was prepared in a similar procedure to Example 60,
step 5.
Step 4:
(E)-6-(but-2-en-1-yl)-4-(4-chloro-5-(morpholine-4-carbonyl)pyridin-2-yl)-2-
-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (5)
##STR00217##
Example 103 was prepared in a similar procedure to Example 60, step
6. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.69 (s, 1H), 8.10 (s,
1H), 7.88-7.80 (m, 1H), 5.84-5.72 (m, 1H), 5.71-5.61 (m, 1H), 4.68
(d, J=5.6 Hz, 2H), 3.87-3/3 (m, 4H), 3.71-3.63 (m, 2H), 3.46-3.36
(m, 2H), 2.45 (s, 3H), 1.87-1.79 (m, 0.8H), 1.70 (d, J=6.1 Hz,
2.2H). LCMS (M+H.sup.+) m/z: 427.
The following compounds were prepared in a similar fashion to
Example 104:
Examples 105-110
TABLE-US-00007 Example IUPAC Name NMR m/z 105 6-[(E)-but-2-enyl]-2-
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta.d9.10 (s, 2 H), 394
methyl-4-[2-(morpholine- 7.45 (d, J = 2.0 Hz, 1 H), 6.31 (s, 0.4
H), 4-carbonyl)pyrimidin-5- 5.78-5.56 (m, 2 H), 4.68-4.66 (m, 2 H),
yl]-1H-pyrrolo[2,3- 3.80 (d, J = 2.0 Hz, 4 H), 3.69-3.66 (m, 2 H),
c]pyridin-7-one 3.47-3.45 (m, 2 H), 2.43 (s, 3 H), 1.82 (dd, J =
0.6 Hz, 0.6 H), 1.69 (d, J = 3.6 Hz, 2.6 H). 106
5-[6-[(E)-but-2-enyl]-2- .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
417 methyl-7-oxo-1H- 11.39-11.28 (m, 1 H), 7.91 (s, 1 H), 7.88-7.85
(m, 1 H), pyrrolo[2,3-c]pyridin-4- 7.55 (d, J = 8.0 Hz, 1 H), 7.02
(s, 1 H), yl]-2-(morpholine-4- 6.19 (s, 1 H), 5.80-5.59 (m, 2 H),
4.85-4.71 (m, 2 carbonyl)benzonitrile H), 3.87 (d, J = 6.0 Hz, 4
H), 3.75 (s, 2 H), 3.43 (s, 2 H), 2.51 (s, 3 H), 1.74 (d, J = 6.0
Hz, 3 H). 107 6-[(E)-but-2-enyl]-4-[4- .sup.1H NMR (400 MHz,
CDCl.sub.3) d 7.34 (d, J = 7.78 Hz, 367 (1-hydroxy-1-methyl- 1 H),
7.22 (s, 1 H), 7.08 (d, J = 8.03 Hz, ethyl)-2-methoxy- 1 H),
7.00-7.03 (m, 1 H), 5.98 (s, 1 H), phenyl]-2-methyl-1H- 5.65-5.70
(m, 1 H), 4.65 (d, J = 4.77 Hz, 2 pyrrolo[2,3-c]pyridin-7- H), 3.84
(s, 3 H), 2.42 (s, 3 H), 1.84 (s, 1 H), one 1.81 (d, J = 7.28 Hz, 1
H), 1.71 (d, J = 4.77 Hz, 2 H), 1.65 (s, 6 H). 108
6-[(E)-but-2-enyl]-4-[2,5- .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.31 (s, 1 H), 452 dimethoxy-4- 6.97 (d, J = 13.2 Hz, 1 H),
6.55 (s, 2 H), (morpholine-4- 6.48 (t, J = 9.4 Hz, 1 H), 6.18-5.68
(m, 2 H), carbonyl)phenyl]-2- 4.95-4.83 (m, 2 H), 3.90-3.66 (m, 10
H), 3.37 (d, J = 28 Hz, methyl-1H-pyrrolo[2,3- 2 H), 2.57 (s, 3 H),
1.85 (d, J = 6.0 Hz, c]pyridin-7-one 0.6 H), 1.75 (d, J = 4.4 Hz,
2.3 H). 109 3-[6-[(E)-but-2-enyl]-2- .sup.1H NMR (400 MHz,
CD.sub.3OD) d 8.69 (s, 1 H), 444 methyl-7-oxo-1H- 8.64 (s, 1 H),
8.53 (s, 1 H),7.96-7.91 (m, 2 H), pyrrolo[2,3-c]pyridin-4-
7.23-7.17 (m, 2 H), 5.76-5.59 (m, 2 H), yl]-4-methoxy-N- 4.81-4.66
(m, 4 H), 3.84 (s, 3 H), 2.40 (s, 3 (pyrazin-2- H), 1.81-1.68 (m, 3
H). ylmethyl)benzamide 110 6-but-2-enyl-4-[3- .sup.1H NMR (4:1 E/Z
mixture) (400 MHz, 436 methoxy-5-(4- DMSO-d6) d 11.76 (br. s, 1H),
8.23 (d, J = 1.71 Hz, methylpiperazine-1- 1H), 7.62 (s, 1H), 7.50
(d, J = 1.71 Hz, carbonyl)-2-pyridyl]-2- 1H), 6.25 (dd, J = 0.98,
2.20 Hz, 1H), methyl-1H-pyrrolo[2,3- 5.57-5.73 (m, 2H), 4.58 (d, J
= 5.13 Hz, c]pyridin-7-one 2H), 3.85 (s, 3H), 3.54-3.73 (m, 2H),
3.39-3.53 (m, 2H), 2.32-2.47 (m, 4H), 2.31 (s, 3H), 2.21 (s, 3H),
1.67 (d, J = 5.13 Hz, 3H).
Example 111
6-[(E)-but-2-enyl]-4-[6-chloro-5-(morpholine-4-carbonyl)-2-pyridyl]-2-meth-
yl-1H-pyrrolo[2,3-c]pyridin-7-one
##STR00218## Step 1:
(2-chloropyridin-3-yl)(morpholino)methanone
##STR00219##
This compound was prepared in a similar procedure to Example 55,
step 1.
Step 2:
2-chloro-3-(morpholine-4-carbonyl)pyridine 1-oxide
##STR00220##
To a mixture of (2-chloro-3-pyridyl)-morpholino-methanone (3.00 g,
13.24 mmol) in trifluoroacetic acid (15 mL) was added hydrogen
peroxide (5.90 g, 52.04 mmol) in one portion under N.sub.2. The
mixture was stirred at 65.degree. C. for 16 hrs. The mixture was
concentrated under reduced pressure and the residue was adjusted to
pH 8 with saturated NaHCO.sub.3 solution. The mixture was extracted
with DCM. The combined organics were dried with anhydrous sodium
sulfate and concentrated under reduced pressure to afford
(2-chloro-1-oxido-pyridin-1-ium-3-yl)-morpholino-methanone (2.40 g,
crude) as a yellow solid.
Step 3:
(6-bromo-2-chloropyridin-3-yl)(morpholino)methanone
##STR00221##
A solution of
(2-chloro-1-oxido-pyridin-1-ium-3-yl)-morpholino-methanone (2.00 g,
8.24 mmol) and POBr.sub.3 (9.45 g, 32.96 mmol) in CH.sub.3CN (80
mL) was stirred at 70.degree. C. for 16 hrs. The mixture was
concentrated under reduced pressure and quenched with water (20
mL). The aqueous layer was extracted with DCM, and the combined
organic layers were washed with saturated sodium bicarbonate and
brine (30 mL), then dried over sodium sulfate and concentrated
under reduced pressure. The residue was purified by silica gel
chromatography (Petroleum ether/ethyl acetate=30/1, 20/1) to afford
(6-bromo-2-chloro-3-pyridyl)-morpholino-methanone (300 mg, 0.87
mmol, 11%) as a yellow oil.
Step 4:
(E)-6-(but-2-en-1-yl)-4-(6-chloro-5-(morpholine-4-carbonyl)pyridin-2-yl)-2-
-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
##STR00222##
Example 111 was Prepared in a Similar Procedure to Example 85, Step
2
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.88-7.82 (m, 3H), 6.68
(s, 1H), 5.78-5.66 (m, 2H), 4.69-4.68 (m, 2H), 3.79 (s, 4H),
3.71-3.64 (m, 2H), 3.39-3.34 (m, 2H), 2.45 (s, 3H), 1.71 (d, J=6.0
Hz, 3H). LCMS (M+H.sup.+) m/z: 427.
Example 112
1-[4-[6-[(E)-but-2-enyl]-2-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-2-c-
hloro-benzoyl]piperidine-4-carboxylic acid
##STR00223## Step 1:
methyl 1-(4-bromo-2-chlorobenzoyl)piperidine-4-carboxylate
##STR00224##
This compound was prepared in a similar procedure to Example 55,
step 1.
Step 2:
methyl
1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)-
piperidine-4-carboxylate
##STR00225##
This compound was prepared in a similar procedure to Example 55,
step 3.
Step 3:
(E)-methyl1-(4-(6-(but-2-en-1-yl)-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,-
3-c]pyridin-4-yl)-2-chlorobenzoyl)piperidine-4-carboxylate
##STR00226##
This compound was prepared in a similar procedure to Example 1.
Step 4:
(E)-1-(4-(6-(but-2-en-1-yl)-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]py-
ridin-4-yl)-2-chlorobenzoyl)piperidine-4-carboxylic acid
##STR00227##
Example 112 was Prepared in a Similar Procedure to Example 60, Step
5
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.69 (d, J=6.0 Hz, 1H),
7.65-7.61 (m, 1H), 7.45-7.43 (m, 1H), 7.28 (s, 1H), 6.25 (s, 1H),
5.77-5.67 (m, 2H), 4.66-4.65 (m, 2H), 4.54-4.51 (m, 1H), 3.52-3.48
(m, 1H), 3.19-3.01 (m, 2H), 2.66-2.64 (m, 1H), 2.43 (s, 3H),
2.09-2.06 (m, 1H), 1.92-1.89 (m, 1H), 1.84-1.69 (m, 5H). LCMS
(M+H.sup.+) m/z: 468.
Example 113
(E)-1-(4-(6-(but-2-en-1-yl)-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]py-
ridin-4-yl)-2-chlorobenzoyl)piperidine-4-carboxamide
##STR00228##
Example 113 was Prepared in a Similar Procedure to Example 60, Step
6
.sup.1HNMR (400 MHz, CD.sub.3OD) .delta. 7.71 (d, J=6.8 Hz, 2H),
7.67-7.63 (m, 1H), 7.51-7.39 (m, 1H), 7.30 (s, 1H), 6.28 (s, 1H),
5.80-5.66 (m, 2H), 4.83-4.82 (m, 1H), 4.73-4.68 (m, 3H), 3.56 (s,
1H), 3.24-3.14 (m, 1H), 3.02-2.96 (m, 1H), 2.59-2.56 (m, 2H), 2.46
(s, 3H), 2.00-1.98 (m, 1H), 1.87-1.63 (m, 6H). LCMS (M+H.sup.+)
m/z: 467.
Example 114
6-[(E)-but-2-enyl]-4-[3-isopropoxy-4-(morpholine-4-carbonyl)phenyl]-2-meth-
yl-1H-pyrrolo[2,3-c]pyridin-7-one
##STR00229## Step 1:
(4-bromo-2-methoxy-phenyl)-morpholino-methanone
##STR00230##
This compound was prepared in a similar procedure to Example 55,
Step 1.
Step 2:
(4-bromo-2-hydroxy-phenyl)-morpholino-methanone
##STR00231##
To a mixture of (4-bromo-2-methoxy-phenyl)-morpholino-methanone
(500 mg, 1.67 mmol) in dichloromethane (10 mL) was added BBr.sub.3
(835 mg, 3.33 mmol) at 0.degree. C. under N.sub.2. The mixture was
stirred at 80.degree. C. for 16 hrs. The mixture was poured into
H.sub.2O (50 mL) and extracted with DCM. The combined organic
layers were dried with sodium sulfate and concentrated under
reduced pressure to give
(4-bromo-2-hydroxy-phenyl)-morpholino-methanone (400 mg, crude) as
a white solid.
Step 3:
(4-bromo-2-isopropoxy-phenyl)-morpholino-methanone
##STR00232##
To a mixture of (4-bromo-2-hydroxy-phenyl)-morpholino-methanone
(300 mg, 1.05 mmol) and 2-bromopropane (155 mg, 1.26 mmol) in DMF
(8 mL) was added potassium carbonate (435 mg, 3.15 mmol). The
mixture was stirred at 80.degree. C. for 16 hrs. TLC showed the
reaction was completed. The mixture was poured into H.sub.2O (80
mL), then extracted with ethyl acetate. The combined organic layers
were dried with sodium sulfate and concentrated under reduced
pressure. The crude product was purified by silica gel
chromatography (Petroleum ether/ethyl acetate=4/1) to give
(4-bromo-2-isopropoxy-phenyl)-morpholino-methanone (344 mg, 1.05
mmol, 100%) as a white solid.
Step 4:
[2-isopropoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-morph-
olino-methanone
##STR00233##
This compound was prepared in a similar procedure to Example 55,
Step 3.
Step 5:
6-[(E)-but-2-enyl]-4-[3-isopropoxy-4-(morpholine-4-carbonyl)phenyl]-2-meth-
yl-1H-pyrrolo[2,3-c]pyridin-7-one
##STR00234##
This compound was prepared in a similar procedure to Example 85,
Step 3. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 10.90-10.77 (m,
1H), 7.34 (d, 0.1=8.0 Hz, 1H), 7.17-7.14 (m, 1H), 7.08 (s, 1H),
6.97 (s, 1H), 6.19 (d, J=1.2 Hz, 1H), 5.80-5.58 (m, 2H), 4.81 (d,
J=6.8 Hz, 0.36H), 4.69 (d, J=4.0 Hz, 1.40H), 4.66-4.60 (m, 1H),
3.89-3.86 (m, 1H), 3.78-3.72 (m, 4H), 3.62-3.61 (m, 1H), 3.44-3.27
(m, 2H), 2.48 (s, 3H), 1.84-1.83 (m, 0.53H), 1.72 (d, J=5.2 Hz,
2.36H), 1.37 (dd, J=10.8, 6H). LCMS (M+H.sup.+) m/z: 450.
Example 115 was Prepared in a Similar Procedure to Example 114
TABLE-US-00008 Example IUPAC Name NMR m/z 115 6-[(E)-but-2-enyl]-4-
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 10.20 (s, 1 H), 462 [3-
7.35 (d, J = 7.6 Hz, 1 H), 7.16 (t, J = 3.8 Hz, 1
(cyclopropylmethoxy)- H), 7.03-6.96 (m, 2 H), 6.20 (s, 1 H),
4-(morpholine-4- 5.75-5.63 (m, 2 H), 4.79 (d, J = 7.2 Hz, 0.5 H),
4.67 (d, J = 4.4 Hz, carbonyl)phenyl]-2- 1.5 H), 3.93-3.33 (m, 11
H), 2.47 (s, 3 methyl-1H- H), 1.83 (d, J = 6.0 Hz, 0.6 H), 1.71 (d,
J = 5.2 Hz, pyrrolo[2,3-c]pyridin- 2.2 H), 1.28 (t, J = 6.0 Hz, 1
H), 0.65 (d, J = 7.6 Hz, 7-one 2 H), 0.36 (s, 2 H).
Example 116
(E)-6-(but-2-en-1-yl)-4-(3-chloro-4-(piperazine-1-carbonyl)phenyl)-2-methy-
l-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
##STR00235## Step 1:
(E)-tert-butyl
4-(4-(6-(but-2-en-1-yl)-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-e]pyrid-
in-4-yl)-2-chlorobenzoyl)piperazine-1-carboxylate
##STR00236##
This compound was prepared in a similar procedure to Example 85,
Step 2.
Step 2:
(E)-6-(but-2-en-1-yl)-4-(3-chloro-4-(piperazine-1-carbonyl)phenyl)-2-methy-
l-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
##STR00237##
To a mixture of tert-butyl
4-[4-[6-[(E)-but-2-enyl]-2-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-2--
chloro-benzoyl]piperazine-1-carboxylate (200 mg, 380.9 umol) in
methanol (4 mL) was added HCl/methanol (4 M, 1.00 mL) solution in
one portion under N.sub.2. The mixture was stirred at 20.degree. C.
for 4 hrs. The mixture was then concentrated under reduced
pressure. The residue was purified by Prep-HPLC (Column: Waters
Xbridge C18 150*20 mm*5 um. Mobile phase A: water with 0.5% (v/v)
NH.sub.3.H.sub.2O. Mobile phase B: MeOH, Gradient: 40-70%. Flow
rate: 25 ml/min) to afford
6-[(E)-but-2-enyl]-4-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-2-methyl--
1H-pyrrolo[2,3-c]pyridin-7-one (66 mg, 150 umol, 40%) as a white
solid. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 7.70 (s, 1H),
7.65-7.63 (m, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.28 (s, 1H), 6.26 (s,
1H), 5.78-5.68 (m, 2H), 4.67 (d, J=6.4 Hz, 2H), 3.79-3.77 (m, 2H),
2.94-2.76 (m, 5H), 2.44 (s, 3H), 1.72 (d, J=5.6 Hz, 3H). LCMS
(M+H.sup.+) m/z: 425.
Example 117
(E)-4-(4-(3-(3-amino-1H-pyrazol-1-yl)azetidine-1-carbonyl)-3-chlorophenyl)-
-6-(but-2-en-1-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
##STR00238##
Example 117 was Prepared in a Similar Procedure to Example 60, Step
6
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.69 (s, 1H), 7.64-7.62
(m, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.40 (d, J=6.4 Hz, 1H), 7.27 (s,
1H), 6.24 (s, 1H), 5.73-5.67 (m, 2H), 5.63 (d, J=2.4 Hz, 1H),
5.10-5.09 (m, 1H), 4.60-4.55 (m, 3H), 4.49-4.48 (m, 1H), 4.40-4.38
(m, 2H), 2.43 (s, 3H), 1.70 (d, J=5.6 Hz, 3H). LCMS (M+H.sup.+)
m/z: 477.
Example 118 was Prepared in a Similar Procedure to Example 117
TABLE-US-00009 Example IUPAC Name NMR m/z 118 4-[4-[3-(3- .sup.1H
NMR (400 MHz, D.sub.2O) .delta. 7.62 (d, J = 2.4 Hz, 443
aminopyrazol-1- 1 H), 7.42-7.28 (m, 2 H), 7.18-7.08 (m, 2 H),
yl)azetidine-1- 6.83-6.73 (m, 1 H), 6.21-6.11 (m, 1 H),
carbonyl]phenyl]-6- 5.94-5.84 (m, 1 H), 5.39-5.26 (m, 2 H),
5.15-5.03 (m, [(E)-but-2-enyl]-2- 2 H), 4.54-4.43 (m, 2 H),
4.42-4.29 (m, 2 H), methyl-1H-pyrrolo[2,3- 4.25 (br. s, 1 H), 2.16
(s, 3 H), 1.50 (d, J = 6.4 Hz, c]pyridin-7-one 0.74 H), 1.41 (d, J
= 3.4 Hz, 2.36 H).
Example 119
(E)-6-(but-2-en-1-yl)-4-(4-(2-hydroxypropan-2-yl)-2,5-dimethoxyphenyl)-2-m-
ethyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
##STR00239## Step 1:
2-(4-bromo-2,5-dimethoxyphenyl)propan-2-ol
##STR00240##
To a solution of 1-(4-bromo-2,5-dimethoxy-phenyl)ethanone (500 mg,
1.93 mmol) in tetrahydrofuran (10 mL) was added dropwise
methylmagnesium bromide (3 M, 2.00 mL) at -78.degree. C. The
mixture was stirred at -78.degree. C. for 1 hr, then the mixture
was warmed to 0.degree. C. and stirred for 1 hr. The mixture was
quenched with saturated NH.sub.4Cl solution and the aqueous phase
was extracted with ethyl acetate. The combined organic phases were
washed with brine (50 mL), dried with anhydrous sodium sulfate, and
concentrated under reduced pressure. The residue was purified by
silica gel chromatography (Petroleum ether/ethyl acetate=20/1,
10/1) to give 2-(4-bromo-2,5-dimethoxy-phenyl)propan-2-ol (300 mg,
0.98 mmol, 51% yield) as a yellow oil.
Step 2:
(E)-6-(but-2-en-1-yl)-4-(4-(2-hydroxypropan-2-yl)-2,5-dimethoxyphenyl)-2-m-
ethyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
##STR00241##
Example 119 was Prepared in a Similar Procedure to Example 85, Step
2
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.32 (s, 1H), 7.13-7.11
(m, 1H), 6.95 (s, 1H), 5.96 (s, 1H), 5.75-5.66 (m, 2H), 4.62 (d,
J=5.2 Hz, 2H), 3.82 (s, 3H), 3.72 (s, 3H), 2.39 (s, 3H), 1.71 (d,
J=5.6 Hz, 3H), 1.61 (s, 6H). LCMS (M+H.sup.+) m/z: 397.
Example 120
3-[6-[(E)-but-2-enyl]-2-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-4-meth-
oxy-N-(pyrimidin-5-ylmethyl)benzamide
##STR00242## Step 1:
5-(azidomethyl)pyrimidine
##STR00243##
To a mixture of pyrimidin-5-ylmethanol (800 mg, 7.27 mmol) in DCM
(30 mL) and toluene (25 mL) was added DBU (2.21 g, 14.5 mmol) and
DPPA (4.00 g, 14.5 mmol). The mixture was stirred at 25.degree. C.
for 16 hrs. The mixture was then concentrated under reduced
pressure. The residue was purified by silica gel chromatography
(Petroleum ether/ethyl acetate=4/1) to give
5-(azidomethyl)pyrimidine (1.20 g, crude) as a colorless oil.
Step 2:
Pyrimidin-5-ylmethanamine
##STR00244##
To a mixture of 5-(azidomethyl)pyrimidine (600.0 mg, 4.44 mmol) in
THF (15 mL) was added triphenylphosphine (2.33 g, 8.88 mmol) and
water (160.0 mg, 8.88 mmol). The mixture was stirred at 25.degree.
C. for 16 hr. The mixture was concentrated under reduced pressure,
then the residue was partitioned with water and DCM. The phases
were separated, and the aqueous phase was adjusted to pH=8 with
sat. sodium bicarbonate. The mixture was lyophilized to give
pyrimidin-5-ylmethanamine (1.10 g, crude) as a white solid.
Step 3:
3-bromo-4-methoxy-N-(pyrimidin-5-ylmethyl)benzamide
##STR00245##
This compound was prepared in a similar procedure to Example 55,
Step 1.
Step 4:
3-[6-[(E)-but-2-enyl]-2-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-4-meth-
oxy-N-(pyrimidin-5-ylmethyl)benzamide
##STR00246##
Example 120 was Prepared in a Similar Procedure to Example 85, Step
2
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 11.99 (d, J=13.6 Hz, 1H),
9.12 (s, 1H), 8.90 (s, 2 IT), 8.28 (s, 1H), 8.09-8.01 (m, 2H), 7.35
(s, 1H), 7.07 (d, J=8.4 Hz, 1H), 5.99 (s, 1H), 5.86-5.81 (m, 1H),
5.64-5.55 (m, 1H), 4.79-4.62 (m, 4H), 3.82 (s, 3H), 2.30 (d, J=5.2
Hz, 3H), 1.78 (d, J=6.8 Hz, 0.6H), 1.71 (d, J=6.0 Hz, 2.4H). LCMS
(M+H.sup.+) m/z: 444.
Example 121
6-butyl-4-[2,5-dimethoxy-4-(morpholine-4-carbonyl)phenyl]-2-methyl-1H-pyrr-
olo[2,3-c]pyridin-7-one
##STR00247##
To a solution of
6-[(E)-but-2-enyl]-4-[2,5-dimethoxy-4-(morpholine-4-carbonyl)
phenyl]-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-one (Example 108, 30.0
mg, 66.4 umol) in methanol (2 mL) was added Pd/C (7.0 mg, 6.6
umol). The mixture was degassed under vacuum and purged with
H.sub.2. The mixture was stirred under H.sub.2 atmosphere at
80.degree. C. for 12 hr, then the mixture was filtered and the
filtrate was concentrated in vacuum. The residue was purified by
silica gel chromatography (Dichloromethane: Methanol-20:1) to
afford the crude product.
The crude product was purified by Pre-HPLC (Column: Waters Xbridge
C18 150*20 mm*5 um; Mobile phase A: water with 0.05% ammonia
solution; Mobile phase B: CH.sub.3CN; Gradient: 14-44% B, 10 min)
to afford
6-butyl-4-[2,5-dimethoxy-4-(morpholine-4-carbonyl)phenyl]-2-methyl-1H-pyr-
rolo[2,3-c]pyridin-7-one (4.0 mg, 8.8 umol, 13% yield) as white
solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.05 (s, 1H), 6.99
(s, 1H), 6.95 (s, 1H), 5.98 (s, 1H), 4.09 (t, J 7.3 Hz, 2H),
3.60-3.96 (m, 11H), 3.30-3.47 (m, 1H), 2.45 (s, 3H), 1.77-1.86 (m,
2H), 1.44 (d, J=7.5 Hz, 2H), 0.97 (t, J=7.3 Hz, 3H). LCMS (M+Fr)
m/z: 454.
The following compounds were prepared in a similar fashion to
Example 121:
Examples 122-123
TABLE-US-00010 Example IUPAC Name NMR m/z 122 6-butyl-4-[3-methoxy-
.sup.1H NMR (400 MHz, DMSO-d6) d11.72 (br. s, 438 5-(4- 1H), 8.23
(d, J = 1.71 Hz, 1H), 7.66 (s, 1H), methylpiperazine-1- 7.50 (d, J
= 1.71 Hz, 1H), 6.24 (dd, J = 0.98, 2.20 Hz, carbonyl)-2-pyridyl]-
1H), 4.02 (t, J = 7.08 Hz, 2H), 3.86 (s, 3H), 2-methyl-1H- 3.57 (s,
2H), 3.38-3.54 (m, 2H), 2.31-2.45 (m, 4H), pyrrolo[2,3-c]pyridin-
2.31 (s, 3H), 2.22 (s, 3H), 1.67 (quin, J = 7.26 Hz, 7-one 2H),
1.27-1.38 (m, 2H), 0.92 (t, J = 7.32 Hz, 3H). 123
6-butyl-4-[3-methoxy- .sup.1H NMR (400 MHz, DMSO-d6) d 11.73 (br.
s., 425 5-(morpholine-4- 1H), 8.27 (d, J = 1.71 Hz, 1H), 7.66 (s,
1H), carbonyl)-2-pyridyl]- 7.54 (d, J = 1.71 Hz, 1H), 6.24 (dd, J =
0.85, 2.08 Hz, 2-methyl-1H- 1H), 4.02 (t, J = 6.96 Hz, 2H), 3.87
(s, 3H), pyrrolo[2,3-c]pyridin- 3.41-3.89 (m, 8H), 2.31 (s, 3H),
1.67 (quin, J = 7.26 Hz, 7-one 2H), 1.33 (qd, J = 7.49, 14.89 Hz,
2H), 0.92 (t, J = 7.45 Hz, 3H).
Example 124
Synthesis of biotinylated probe compound (1000) for TAF assay
described below
##STR00248## Step 1:
2-methoxy-4-methyl-3-nitropyridine
##STR00249##
A solution of 2-chloro-4-methyl-3-nitropyridine (250 g, 1.45 mol)
in methanol (1.0 L) was added dropwise (2 h) to a stirred and
cooled (0.degree. C.) solution of sodium methoxide (250 g, 4.63
mol) in methanol (850 mL). After addition, the mixture was heated
to reflux for 23 h, at which time TLC indicated the reaction had
gone to completion. The mixture was concentrated under reduced
pressure to a volume of approximately 900 mL, and quenched by
addition of water (1.5 L). The resulting solid was collected by
filtration, washed with water and dried under reduced pressure to
give the title compound (250 g, 100% yield) as a brown solid.
.sup.1H NMR (400 MHz, DMSO-d6): .delta. 8.22 (d, 0.1=5.2 Hz, 1H),
7.10 (d, J=5.6 Hz, 1H), 3.92 (s, 3H), 2.26 (s, 3H).
Step 2:
5-bromo-2-methoxy-4-methyl-3-nitropyridine
##STR00250##
Sodium acetate (365 g, 5.37 mol) was added to a stirred solution of
2-methoxy-4-methyl-3-nitropyridine (250 g, 1.49 mol) in acetic acid
(1.5 L) at ambient temperature and then Br.sub.2 (639 g, 4.00 mol)
was added dropwise (30 min). After addition, the mixture was heated
at 80.degree. C. for 12 h, at which time TLC indicated the reaction
had gone to completion. The mixture was cooled (0.degree. C.) and
quenched by sequential addition of 10% aqueous (1.5 L) and
saturated aqueous Na.sub.2SO.sub.3 (1.5 L). The resulting solid was
collected by filtration washed with water, and dried under reduced
pressure to give the title compound (302 g, 82.2% yield) as a light
yellow solid. .sup.1H NMR (400 MHz, DMSO-d6): .delta. 8.25 (s, 1H),
3.94 (s, 3H), 2.29 (s, 3H).
Step 3:
(E)-2-(5-bromo-2-methoxy-3-nitro-4-pyridyl)-N,N-dimethyl-ethenamine
##STR00251##
DMF-DMA (600 mL) was slowly added to a stirred and heated
(80.degree. C.) solution of
5-bromo-2-methoxy-4-methyl-3-nitropyridine (134 g, 0.54 mol) in DMF
(1.1 L). After addition, the mixture was heated at 95.degree. C.
for 5 h, at which time TLC indicated the reaction had gone to
completion. The mixture was cooled to room temperature and poured
into ice-cold water (3 L). The resulting red solid was collected by
filtration, washed with water, and dried under reduced pressure to
give the title compound (167 g, 100% yield) as red solid. .sup.1H
NMR (400 MHz, DMSO-d6): .delta. 8.24 (s, 1H), 7.05 (d, J=13.6 Hz,
1H), 7.05 (d, J=13.6 Hz, 1H), 4.80 (d, 1=13.2 Hz, 1H), 3.88 (s,
3H), 2.90 (s, 6H).
Step 4:
4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine
##STR00252##
A mixture of
2-(5-bromo-2-methoxy-3-nitropyridin-4-yl)-N,N-dimethylethenamine
(50.0 g, 165 mmol), Fe (50.0 g, 893 mmol) and NH.sub.4Cl (50.0 g,
943 mmol) in methanol/H.sub.2O (1900/250 mL) was heated at reflux
for 7 h, at which time LCMS indicated that the reaction had gone to
completion. The mixture was filtered while hot and the cake was
washed with methanol (3.times.200 mL). The combined filtrate was
concentrated under reduced pressure, and the resulting residue was
purified by silica gel chromatography (petroleum ether:Ethyl
acetate=5:1) to give the crude product. This crude material was
triturated with acetonitrile to give the title compound (37.4 g,
99.5% yield) as a light brown solid. LCMS M/Z (M+H) 226.7,
228.7.
Step 5:
4-bromo-7-methoxy-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine
##STR00253##
A solution of 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine (34.3 g,
0.15 mol) in THF (700 mL) was added dropwise to a stirred and
cooled (0.degree. C.) solution of sodium hydride (60%, 19.2 g, 0.48
mol) in THF (700 mL). After addition, the mixture was stirred at
room temperature for 1 h, and then cooled again to 0.degree. C.
Tosyl chloride (38.0 g, 0.20 mol) in THF (700 mL) was added
dropwise and the resulting mixture was stirred at ambient
temperature for 2 h. The reaction was quenched by addition of
saturated aqueous ammonium chloride (1.0 L), and then extracted
with ethyl acetate (3.times.600 mL). The combined organic extracts
were dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure. The residue was triturated with acetonitrile to give the
title compound (51.2 g, 88.9% yield) as a brown solid. This crude
material was used in the next step without further
purification.
Step 6:
4-bromo-1-(p-tolylsulfonyl)-6H-pyrrolo[2,3-c]pyridin-7-one
##STR00254##
HBr (40% aqueous, 1.1 L) was added to a solution of
4-bromo-7-methoxy-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine (102.5
g, 0.27 mol) in ethanol (200 mL). After addition, the mixture was
heated at 90.degree. C. for 2 h, at which time TLC indicated that
the reaction had gone to completion. The mixture was cooled to
0.degree. C. and the resulting white solid was collected by
filtration. This solid was washed with water and dried under vacuum
to give the title compound (87.5 g, 88.6% yield) as a light brown
solid. .sup.1H NMR (400 MHz, DMSO-d6): .delta. 11.48 (s, 1H), 8.01
(d, J=3.6 Hz, 1H), 8.90 (d, J=8.0 Hz, 2H), 7.38 (d, J 8.0 Hz, 2H),
7.32 (s, 1H), 6.57 (d, J=3.2 Hz, 1H), 2.34 (s, 3H).
Step 7:
4-bromo-6-methyl-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridin-7-one
##STR00255##
Methyl iodide (24.5 g, 172.8 mmol) was added dropwise to a stirred
suspension of 4-bromo-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
(Intermediate A) (16.7 g, 45.5 mmol) and cesium carbonate (17.8 g,
54.6 mmol) in dioxane (250 mL). After addition, the reaction
mixture was stirred at room temperature for 18 h, at which time
LCMS indicated the reaction had gone to completion. The solvent was
evaporated under reduced pressure, and the residue was diluted with
water (200 mL). The mixture was extracted with EtOAc (3.times.200
mL). The combined organic extracts were dried over sodium sulfate,
filtered and concentrated under reduced pressure. The residue was
purified by silica gel chromatography (petroleum ether/ethyl
acetate=3:1) to give the title compound (14.0 g, 81.4% yield) as a
brown solid.
.sup.1H NMR (400 MHz, DMSO-d6): .delta. 8.03 (d, J=3.6 Hz, 1H),
7.92 (d, J=8.4 Hz, 2H), 7.78 (s, 1H), 7.39 (d, J=8.4 Hz, 2H), 6.57
(d, J=3.6 Hz, 1H), 3.35 (s, 3H), 2.35 (s, 3H).
Step 8:
A 50 mL vial was charged with a magnetic stir bar,
4-bromo-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (0.281
g, 0.737 mmol), 1,4-dioxane (3.69 ml, 0.737 mmol), water (0.5 ml,
27.8 mmol), K.sub.2CO.sub.3 (0.306 g, 2.211 mmol),
4-(tertbutoxycarbonylamino)phenylboronic acid (0.227 g, 0.958
mmol), and Pd(PPh.sub.3).sub.4 (0.085 g, 0.074 mmol). The vial was
purged, placed under an atmosphere of nitrogen and heated to
95.degree. C. with stirring for 12 h before being allowed to cool
to room temperature. The reaction was then diluted with water (20
ml). A precipitate formed which was collected via vacuum filtration
using a Buchner funnel. The solids were washed with additional
water (2.times.25 mL), dried, and collected. This material was
suspended in methanol (5 mL) and treated with KOH (200 mg). After 2
h the MeOH was removed in vacuo and the crude material was
suspended in water (20 mL) and the resulting solids were collected
via vacuum filtration using a Buchner funnel. The solids were
washed with additional water, were collected, and dried in vacuo to
afford tert-butyl
4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenylcarbama-
te (362 mg, 0.907 mmol) as a light yellow solid. LCMS M/Z (M+H)
494.
Step 9:
A 50 mL round bottom flask was charged with a magnetic stir bar,
tert-butyl
4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenylcarbama-
te (350 mg, 1.031 mmol), MeOH (2.062 mL, 1.031 mmol), and HCl
(1.031 mL, 4.12 mmol) (4N in dioxane). The reaction was then
allowed to stir at rt for 4 h before being diluted with dioxane (25
mL). A precipitate formed which was collected via vacuum filtration
using a Buchner funnel, washed with additional dioxane, and dried
in vacuo to afford
4-(4-aminophenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (188
mg, 0.786 mmol, 76% yield) as a white solid. LCMS M/Z (M+H)
240.
Step 10:
A 25 mL vial was charged with a magnetic stir bar,
4-(4-aminophenyl)-6-methyl-1Hpyrrolo[2,3-c]pyridin-7(6H)-one (0.038
g, 0.159 mmol), anhydrous DMF (0.794 ml, 0.159 mmol), DIPEA (0.139
ml, 0.794 mmol),
17-oxo-21-((3aS,4S,6aR)-2-oxohexahydro-1Hthieno[3,4-d]imidazol-4-y-
l)-4,7,10,13-tetraoxa-16-azahenicosan-1-oic acid (0.078 g, 0.159
mmol), and HATU (0.075 g, 0.199 mmol). The crude reaction mixture
was directly purified via reverse phase HPLC to afford
N-(4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-1--
(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)-
-3,6,9,12-tetraoxapentadecan-15-amide (31 mg, 0.041 mmol, 26.0%
yield). LCMS M/Z (M+2H)/2 357.
Example 125
Synthesis of biotinylated probe compound (1001) for CECR2 assay
described below
##STR00256## Step 1:
2-methoxy-4-methyl-3-nitropyridine
##STR00257##
A solution of 2-chloro-4-methyl-3-nitropyridine (250 g, 1.45 mol)
in methanol (1.0 L) was added dropwise (2 h) to a stirred and
cooled (0.degree. C.) solution of sodium methoxide (250 g, 4.63
mol) in methanol (850 mL). After addition, the mixture was heated
to reflux for 23 h, at which time TLC indicated the reaction had
gone to completion. The mixture was concentrated under reduced
pressure to a volume of approximately 900 mL, and quenched by
addition of water (1.5 L). The resulting solid was collected by
filtration, washed with water and dried under reduced pressure to
give the title compound (250 g, 100% yield) as a brown solid.
.sup.1H NMR (400 MHz, DMSO-d6): .delta. 8.22 (d, 5.2 Hz, 1H), 7.10
(d, J=5.6 Hz, 1H), 3.92 (s, 3H), 2.26 (s, 3H).
Step 2:
5-bromo-2-methoxy-4-methyl-3-nitropyridine
##STR00258##
Sodium acetate (365 g, 5.37 mol) was added to a stirred solution of
2-methoxy-4-methyl-3-nitropyridine (250 g, 1.49 mol) in acetic acid
(1.5 L) at ambient temperature and then Br.sub.2 (639 g, 4.00 mol)
was added dropwise (30 min). After addition, the mixture was heated
at 80.degree. C. for 12 h, at which time TLC indicated the reaction
had gone to completion. The mixture was cooled (0.degree. C.) and
quenched by sequential addition of 10% aqueous (1.5 L) and
saturated aqueous Na.sub.2SO.sub.3 (1.5 L). The resulting solid was
collected by filtration washed with water, and dried under reduced
pressure to give the title compound (302 g, 82.2% yield) as a light
yellow solid. .sup.1H NMR (400 MHz, DMSO-d6): .delta. 8.25 (s, 1H),
3.94 (s, 3H), 2.29 (s, 3H).
Step 3:
(E)-2-(5-bromo-2-methoxy-3-nitro-4-pyridyl)-N,N-dimethyl-ethenamine
##STR00259##
DMF-DMA (600 mL) was slowly added to a stirred and heated
(80.degree. C.) solution of
5-bromo-2-methoxy-4-methyl-3-nitropyridine (134 g, 0.54 mol) in DMF
(1.1 L). After addition, the mixture was heated at 95.degree. C.
for 5 h, at which time TLC indicated the reaction had gone to
completion. The mixture was cooled to room temperature and poured
into ice-cold water (3 L). The resulting red solid was collected by
filtration, washed with water, and dried under reduced pressure to
give the title compound (167 g, 100% yield) as red solid. .sup.1H
NMR (400 MHz, DMSO-d6): .delta. 8.24 (s, 1H), 7.05 (d, J=13.6 Hz,
1H), 7.05 (d, J=13.6 Hz, 1H), 4.80 (d, J=13.2 Hz, 1H), 3.88 (s,
3H), 2.90 (s, 6H).
Step 4:
4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine
##STR00260##
A mixture of
2-(5-bromo-2-methoxy-3-nitropyridin-4-yl)-N,N-dimethylethenamine
(50.0 g, 165 mmol), Fe (50.0 g, 893 mmol) and NH.sub.4Cl (50.0 g,
943 mmol) in methanol/H.sub.2O (1900/250 mL) was heated at reflux
for 7 h, at which time LCMS indicated that the reaction had gone to
completion. The mixture was filtered while hot and the cake was
washed with methanol (3.times.200 mL). The combined filtrate was
concentrated under reduced pressure, and the resulting residue was
purified by silica gel chromatography (petroleum ether:Ethyl
acetate=5:1) to give the crude product. This crude material was
triturated with acetonitrile to give the title compound (37.4 g,
99.5% yield) as a light brown solid. LCMS M/Z (M+H) 226.7,
228.7.
Step 5:
4-bromo-7-methoxy-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine
##STR00261##
A solution of 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine (34.3 g,
0.15 mol) in THF (700 mL) was added dropwise to a stirred and
cooled (0.degree. C.) solution of sodium hydride (60%, 19.2 g, 0.48
mol) in THF (700 mL). After addition, the mixture was stirred at
room temperature for 1 h, and then cooled again to 0.degree. C.
Tosyl chloride (38.0 g, 0.20 mol) in THF (700 mL) was added
dropwise and the resulting mixture was stirred at ambient
temperature for 2 h. The reaction was quenched by addition of
saturated aqueous ammonium chloride (1.0 L), and then extracted
with ethyl acetate (3.times.600 mL). The combined organic extracts
were dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure. The residue was triturated with acetonitrile to give the
title compound (51.2 g, 88.9% yield) as a brown solid. This crude
material was used in the next step without further
purification.
Step 6:
4-bromo-1-(p-tolylsulfonyl)-6H-pyrrolo[2,3-c]pyridin-7-one
##STR00262##
HBr (40% aqueous, 1.1 L) was added to a solution of
4-bromo-7-methoxy-1-(p-tolylsulfonylpyrrolo[2,3-c]pyridine (102.5
g, 0.27 mol) in ethanol (200 mL). After addition, the mixture was
heated at 90.degree. C. for 2 h, at which time TLC indicated that
the reaction had gone to completion. The mixture was cooled to
0.degree. C. and the resulting white solid was collected by
filtration. This solid was washed with water and dried under vacuum
to give the title compound (87.5 g, 88.6% yield) as a light brown
solid. .sup.1H NMR (400 MHz, DMSO-d6): .delta.11.48 (s, 1H), 8.01
(d, J=3.6 Hz, 1H), 8.90 (d, J=8.0 Hz, 2H), 7.38 (d, J=8.0 Hz, 2H),
7.32 (s, 1H), 6.57 (d, J=3.2 Hz, 1H), 2.34 (s, 3H).
Step 7:
4-bromo-6-methyl-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridin-7-one
##STR00263##
Methyl iodide (24.5 g, 172.8 mmol) was added dropwise to a stirred
suspension of 4-bromo-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one
(Intermediate A) (16.7 g, 45.5 mmol) and cesium carbonate (17.8 g,
54.6 mmol) in dioxane (250 mL). After addition, the reaction
mixture was stirred at room temperature for 18 h, at which time
LCMS indicated the reaction had gone to completion. The solvent was
evaporated under reduced pressure, and the residue was diluted with
water (200 mL). The mixture was extracted with EtOAc (3.times.200
mL). The combined organic extracts were dried over sodium sulfate,
filtered and concentrated under reduced pressure. The residue was
purified by silica gel chromatography (petroleum ether/ethyl
acetate=3:1) to give the title compound (14.0 g, 81.4% yield) as a
brown solid.
.sup.1H NMR (400 MHz, DMSO-d6): .delta. 8.03 (d, J=3.6 Hz, 1H),
7.92 (d, J=8.4 Hz, 2H), 7.78 (s, 1H), 7.39 (d, J=8.4 Hz, 2H), 6.57
(d, J=3.6 Hz, 1H), 3.35 (s, 3H), 2.35 (s, 3H).
Step 8:
A 50 mL vial was charged with a magnetic stir bar,
4-bromo-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (0.281
g, 0.737 mmol), 1,4-dioxane (3.69 ml, 0.737 mmol), water (0.5 ml,
27.8 mmol), K.sub.2CO.sub.3 (0.306 g, 2.211 mmol),
4-(tertbutoxycarbonylamino)phenylboronic acid (0.227 g, 0.958
mmol), and Pd(PPh.sub.3).sub.4 (0.085 g, 0.074 mmol). The vial was
purged, placed under an atmosphere of nitrogen and heated to
95.degree. C. with stirring for 12 h before being allowed to cool
to room temperature. The reaction was then diluted with water (20
ml). A precipitate formed which was collected via vacuum filtration
using a Buchner funnel. The solids were washed with additional
water (2.times.25 mL), dried, and collected. This material was
suspended in methanol (5 mL) and treated with KOH (200 mg). After 2
h the MeOH was removed in vacuo and the crude material was
suspended in water (20 mL) and the resulting solids were collected
via vacuum filtration using a Buchner funnel. The solids were
washed with additional water, were collected, and dried in vacuo to
afford tert-butyl
4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenylcarbama-
te (362 mg, 0.907 mmol) as a light yellow solid. LCMS M/Z (M+H)
494.
Step 9:
A 50 mL round bottom flask was charged with a magnetic stir bar,
tert-butyl
4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenylcarbama-
te (350 mg, 1.031 mmol), MeOH (2.062 mL, 1.031 mmol), and HCl
(1.031 mL, 4.12 mmol) (4N in dioxane). The reaction was then
allowed to stir at rt for 4 h before being diluted with dioxane (25
mL). A precipitate formed which was collected via vacuum filtration
using a Buchner funnel, washed with additional dioxane, and dried
in vacuo to afford
4-(4-aminophenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (188
mg, 0.786 mmol, 76% yield) as a white solid. LCMS M/Z (M+H)
240.
Step 10:
A 25 mL vial was charged with a magnetic stir bar,
4-(4-aminophenyl)-6-methyl-1Hpyrrolo[2,3-c]pyridin-7(6H)-one (0.038
g, 0.159 mmol), anhydrous DMF (0.794 ml, 0.159 mmol), DIPEA (0.139
ml, 0.794 mmol),
17-oxo-21-((3aS,4S,6aR)-2-oxohexahydro-1Hthieno[3,4-d]imidazol-4-y-
l)-4,7,10,13-tetraoxa-16-azahenicosan-1-oic acid (0.078 g, 0.159
mmol), and HATU (0.075 g, 0.199 mmol). The crude reaction mixture
was directly purified via reverse phase HPLC to afford
N-(4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-1--
(5-((3
aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido-
)-3,6,9,12-tetraoxapentadecan-15-amide (31 mg, 0.041 mmol, 26.0%
yield). LCMS M/Z (M+2H)/2 357.
Example 126
The inhibitory activity of representative compounds against
bromodomains can be evaluated using known methods or using one of
the following assay protocols.
IC.sub.50 Measurements for Inhibitors Using BRD4 AlphaLisa Binding
Assay
His/Flag epitope tagged BRD4 BD1.sub.42-168 was cloned, expressed,
and purified to homogeneity. BRD4 binding and inhibition was
assessed by monitoring the engagement of biotinylated
H4-tetraacetyl peptide (New England Peptide, NEP2069-1/13) with the
target using the AlphaLisa technology (Perkin-Elmer). Specifically,
in a 384 well ProxiPlate BRD4(BD1) (30 nM final) was combined with
peptide (200 nM final) in 40 mM HEPES (pH 7.0), 40 mM NaCl, 1 mM
DTT, 0.01% (w/v) BSA, and 0.008% (w/v) Brij-35 either in the
presence of DMSO (final 1.2% DMSO) or compound dilution series in
DMSO. After 20 minutes incubation at room temperature Alpha
streptavidin donor beads and AlphaLisa anti-Flag acceptor beads
were added to a final concentration of 10 ug/mL each. After three
hours equilibration plates were read on an Envision instrument and
IC.sub.50s calculated using a four parameter non-linear curve
fit.
IC.sub.50 measurements for inhibitors using BRD9 AlphaLisa Binding
Assay
His/Flag epitope tagged BRD9.sub.134-239 was cloned, expressed, and
purified to homogeneity. BRD9 binding and inhibition was assessed
by monitoring the engagement of biotinylated H4-tetraacetyl peptide
(New England Peptide, NEP2069-11/13) with the target using the
AlphaLisa technology (Perkin-Elmer). Specifically, in a 384 well
ProxiPlate BRD9 (50 nM final) was combined with peptide (3 nM
final) in 50 mM HEPES (pH 7.5), 150 mM NaCl, 1 mM TCEP, 0.01% (w/v)
BSA, and 0.008% (w/v) Brij-35 either in the presence of DMSO (final
0.8% DMSO) or compound dilution series in DMSO. After 20 minutes
incubation at room temperature AlphaLisa Streptavidin Acceptor
Beads (Perkin-AL125C) and AlphaLisa Nickel donor beads (Perkin AS
10 ID) were added to a final concentration of 15 ug/mL each. After
ninety minutes of equilibration in the dark, the plates were read
on an Envision instrument and IC.sub.50s calculated using a four
parameter non-linear curve fit.
IC.sub.50 Measurements for Inhibitors Using TAF1-BD2 TR-FRET
Binding Assay
His/Flag epitope tagged TAF1-BD2.sub.1504-1635 was cloned,
expressed, and purified to homogeneity. TAF1-BD2 binding and
inhibition was assessed by monitoring the engagement of a
biotinylated small molecule compound 1000 (Example 124) with the
target using the TR-FRET assay technology (Perkin-Elmer).
Specifically, in a 384 well ProxiPlate TAF1-BD2 (6 nM final) was
combined with biotin-ligand (50 nM final) in 50 mM HEPES (pH 7.5),
50 mM NaCl, 1 mM TCEP, 0.01% (w/v) BSA, and 0.008% (w/v) Brij-35
either in the presence of DMSO (final 0.2% DMSO) or compound
dilution series in DMSO. After 10 minutes incubation at room
temperature, a mixture Eu-W1024 Anti-6.times.His antibody (Perkin
Elmer AD0110) and SureLight.TM. Allophycocyanin-Streptavidin
(APC-SA, Perkin Elmer CR130-100) were added to a final
concentrations of 0.2 nMolar antibody and 25 nMolar APC-SA,
respectively. After twenty minutes of equilibration, the plates
were read on an Envision instrument and IC.sub.50s calculated using
a four parameter non-linear curve fit. Novel compound 1000 and the
TAF1-BD2 TR-FRET Binding Assay described above represent additional
embodiments of the invention.
IC50 Measurements for Inhibitors Using CECR2 TR-FRET Binding
Assay
His/Flag epitope tagged CECR2.sub.424-538 was cloned, expressed,
and purified to homogeneity. CECR2 binding and inhibition was
assessed by monitoring the engagement of a biotinylated small
molecule compound 1001 (Example 125) with the target using the
TR-FRET assay technology (Perkin-Elmer). Specifically, in a 384
well ProxiPlate CECR2 (1.5 nM final) was combined with
biotin-ligand (25 nM final) in 50 mM HEPES (pH 7.5), 50 mM NaCl, 1
mM TCEP, 0.01% (w/v) BSA, and 0.008% (w/v) Brij-35 either in the
presence of DMSO (final 0.2% DMSO) or compound dilution series in
DMSO. After 15 minutes incubation at room temperature, a mixture
Eu-W1024 Anti-6.times.His antibody (Perkin Elmer AD0110) and
SureLight.TM. Allophycocyanin-Streptavidin (APC-SA, Perkin Elmer
CR130-100) were added to a final concentrations of 0.2 nMolar
antibody and 12.5 nMolar APC-SA, respectively. After forty minutes
of equilibration, the plates were read on an Envision instrument
and IC.sub.50s calculated using a four parameter non-linear curve
fit. Novel compound 1001 and the CECR2 TR-FRET Binding Assay
described above represent additional embodiments of the
invention.
Data for representative compounds of formula (I) from the four
assays described above is provided in the following table.
TABLE-US-00011 Example IC50 (uM) Assay 2 2.6 BRD4 4 2.1 BRD4 5 6.4
BRD4 7 2.7 BRD4 9 15 BRD4 11 3.6 BRD4 12 12 BRD4 13 4.5 BRD4 16 8.0
BRD4 20 0.89 BRD4 22 3.0 BRD4 23 2.1 BRD4 26 0.83 BRD4 28 0.51 BRD4
31 1.6 BRD4 32 0.33 BRD4 35 0.72 BRD4 38 1.4 BRD4 39 1.2 BRD4 40
1.8 BRD4 45 8.4 BRD4 63 0.98 BRD4 65 1.6 BRD4 69 0.32 BRD4 75 1.3
BRD4 76 1.2 BRD4 86 2.3 BRD4 84 1.9 BRD4 10 0.32 BRD9 19 0.094 BRD9
24 0.029 BRD9 27 0.039 BRD9 30 0.51 BRD9 34 0.022 BRD9 37 0.013
BRD9 41 0.13 BRD9 42 0.082 BRD9 46 0.046 BRD9 51 0.013 BRD9 52
0.046 BRD9 64 0.056 BRD9 66 0.028 BRD9 67 0.035 BRD9 68 0.039 BRD9
70 0.028 BRD9 72 0.023 BRD9 73 0.035 BRD9 74 0.027 BRD9 78 0.065
BRD9 79 0.020 BRD9 80 0.073 BRD9 81 0.017 BRD9 82 0.043 BRD9 83
0.28 BRD9 87 0.066 BRD9 88 0.30 BRD9 90 0.013 BRD9 91 0.013 BRD9 92
0.010 BRD9 93 0.034 BRD9 94 0.003 BRD9 95 0.005 BRD9 98 0.032 BRD9
99 0.009 BRD9 100 0.011 BRD9 101 0.012 BRD9 102 0.009 BRD9 103
0.046 BRD9 104 0.022 BRD9 105 0.083 BRD9 106 0.006 BRD9 107 0.10
BRD9 108 0.004 BRD9 109 0.006 BRD9 110 0.039 BRD9 111 0.069 BRD9
112 0.008 BRD9 113 0.003 BRD9 114 0.003 BRD9 115 0.005 BRD9 116
0.004 BRD9 117 0.005 BRD9 118 0.009 BRD9 119 0.006 BRD9 120 0.003
BRD9 121 0.017 BRD9 122 0.18 BRD9 123 0.21 BRD9 1 0.39 CECR2 21 3.3
CECR2 33 3.5 CECR2 36 5.7 CECR2 3 5.2 TAF-1 8 0.11 TAF-1 14 2.0
TAF-1 15 9.3 TAF-1 17 5.6 TAF-1 18 0.095 TAF-1 25 0.64 TAF-1 29 4.5
TAF-1 43 2.0 TAF-1 44 1.6 TAF-1 47 3.4 TAF-1 48 0.017 TAF-1 49
0.019 TAF-1 50 0.021 TAF-1 53 0.02 TAF-1 54 0.011 TAF-1 55 0.010
TAF-1 56 0.021 TAF-1 57 0.011 TAF-1 58 0.011 TAF-1 59 0.014 TAF-1
60 0.012 TAF-1 61 0.020 TAF-1 62 0.011 TAF-1 71 1.8 TAF-1 77 0.90
TAF-1 85 0.48 TAF-1 89 0.012 TAF-1 96 0.014 TAF-1 97 0.011
TAF-1
While a number of embodiments have been described, these examples
may be altered to provide other embodiments that utilize the
compounds and methods described herein. Therefore, the scope of
this invention is to be defined by the appended claims rather than
by the specific embodiments that have been represented by way of
example.
* * * * *
References